Sulfoximine substituted quinazolines for pharmaceutical compositions

ABSTRACT

This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I 
                         
wherein Ar, R 1  and R 2  are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Dec. 6, 2013, isnamed 01-2880_SL.txt and is 909 bytes in size.

FIELD OF THE INVENTION

This invention relates to sulfoximine substituted quinazolinederivatives and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a orMNK2b) kinase inhibitors, pharmaceutical compositions containing them,their use in the treatment or amelioration of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) mediated disorders, and intermediatesuseful for their preparation.

Moreover, the present invention relates to the use of sulfoximinesubstituted quinazoline derivatives of the invention for the productionof pharmaceutical compositions for the prophylaxis and/or treatment ofdiseases which can be influenced by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) orfurther variants thereof. Particularly, the present invention relates tothe use of sulfoximine substituted quinazoline derivatives of theinvention for the production of pharmaceutical compositions for theprophylaxis and/or therapy of metabolic diseases, such as diabetes,hyperlipidemia and obesity, hematopoietic disorders, neurodegenerativediseases, kidney damage, inflammatory disorders, and cancer and theirconsecutive complications and disorders associated therewith.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

The present invention is more particularly directed to the treatmentand/or prophylaxis of in particular metabolic diseases of the lipid andcarbohydrate metabolism and the consecutive complications and disordersassociated therewith.

Lipid disorders cover a group of conditions which cause abnormalities inthe level and metabolism of plasma lipids and lipoproteins. Thus,hyperlipidemias are of particular clinical relevance since theyconstitute an important risk factor for the development ofatherosclerosis and subsequent vascular diseases such as coronary heartdisease.

Diabetes mellitus is defined as a chronic hyperglycemia associated withresulting damages to organs and dysfunctions of metabolic processes.Depending on its etiology, one differentiates between several forms ofdiabetes, which are either due to an absolute (lacking or decreasedinsulin secretion) or to a relative lack of insulin. Diabetes mellitusType I (IDDM, insulin-dependent diabetes mellitus) generally occurs inadolescents under 20 years of age. It is assumed to be of auto-immuneetiology, leading to an insulitis with the subsequent destruction of thebeta cells of the islets of Langerhans which are responsible for theinsulin synthesis. In addition, in latent autoimmune diabetes in adults(LADA; Diabetes Care. 8: 1460-1467, 2001) beta cells are being destroyeddue to autoimmune attack. The amount of insulin produced by theremaining pancreatic islet cells is too low, resulting in elevated bloodglucose levels (hyperglycemia). Diabetes mellitus Type II generallyoccurs at an older age. It is above all associated with a resistance toinsulin in the liver and the skeletal muscles, but also with a defect ofthe islets of Langerhans. High blood glucose levels (and also high bloodlipid levels) in turn lead to an impairment of beta cell function and toan increase in beta cell apoptosis.

Diabetes is a very disabling disease, because today's commonanti-diabetic drugs do not control blood sugar levels well enough tocompletely prevent the occurrence of high and low blood sugar levels.Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, heart disease and hyperlipidemia, forwhich persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

In one embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of metabolic diseases of the carbohydrate metabolismand their consecutive complications and disorders such as impairedglucose tolerance, diabetes (preferably diabetes type II), diabeticcomplications such as diabetic gangrene, diabetic arthropathy, diabeticosteopenia, diabetic glomerosclerosis, diabetic nephropathy, diabeticdermopathy, diabetic neuropathy, diabetic cataract and diabeticretinopathy, diabetic maculopathy, diabetic feet syndrome, diabetic comawith or without ketoacidosis, diabetic hyperosmolar coma, hypoglycemiccoma, hyperglycemic coma, diabetic acidosis, diabetic ketoacidosis,intracapillary glomerulonephrosis, Kimmelstiel-Wilson syndrome, diabeticamyotrophy, diabetic autonomic neuropathy, diabetic mononeuropathy,diabetic polyneuropathy, diabetic angiopathies, diabetic peripheralangiopathy, diabetic ulcer, diabetic arthropathy, or obesity indiabetes.

In a further embodiment the compounds and compositions of the presentinvention are useful for the treatment and/or prophylaxis of metabolicdiseases of the lipid metabolism (i.e. lipid disorders) and theirconsecutive complications and disorders such as hypercholesterolemia,familial hypercholesterolemia, Fredrickson's hyperlipoproteinemia,hyperbetalipoproteinemia, hyperlipidemia, low-density-lipoprotein-type[LDL] hyperlipoproteinemia, pure hyperglyceridemia, endogenoushyperglyceridemia, isolated hypercholesterolemia, isolatedhypertroglyceridemia, cardiovascular diseases such as hypertension,ischemia, varicose veins, retinal vein occlusion, atherosclerosis,angina pectoris, myocardial infarction, stenocardia, pulmonaryhypertension, congestive heart failure, glomerulopaty, tubulointestitialdisorders, renal failure, angiostenosis, or cerebrovascular disorders,such as cerebral apoplexy.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of hematopoetic disorders and their consecutivecomplications and disorders such as acute myeloid leukemia (AML), MorbusHodgkin, Non-Hodgkin's lymphoma; hematopoetic disease, acutenon-lymphocytic leukemia (ANLL), myeloproliferative disease acutepromyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL),multiple myeloma, polycythemia vera, lymphoma, acute lymphocyticleukemia (ALL), chronic lymphocytic leukemia (CCL), Wilm's tumor, orEwing's Sarcoma.

In a further embodiment of the present invention the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of cancer and consecutive complications and disorderssuch as cancer of the upper gastrointestinal tract, pancreaticcarcinoma, breast cancer, colon cancer, ovarian carcinoma, cervixcarcinoma, endometrial cancer, brain tumor, testicular cancer, laryngealcarcinoma, osteocarcinoma, prostatic cancer, retinoblastoma, livercarcinoma, lung cancer, neuroblastoma, renal carcinoma, thyroidcarcinoma, esophageal cancer, soft tissue sarcoma, skin cancer,osteosarcoma, rhabdomyosarcoma, bladder cancer, metastatic cancer,cachexia, or pain.

Certain anti-cancer drugs such as cisplatin are linked to serious sideeffects such as nephrotoxicity or ototoxicity, which can be doselimiting. Activation of MNKs has been linked to these side effects. In afurther embodiment of the present invention, the compounds andcompositions of the present invention are useful for the treatmentand/or prophylaxis of ear or kidney damage, in particular for theprevention or treatment of ear and kidney drug induced damage.

Furthermore, the present invention relates to the use of the compoundsaccording to the invention for the production of pharmaceuticalcompositions for the prophylaxis and/or therapy of cytokine relateddiseases.

Such diseases are i.a. inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, infectiousdiseases, neurodegenerative diseases, allergies, or other conditionsassociated with proinflammatory cytokines.

Allergic and inflammatory diseases such as acute or chronicinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, asthma and septic shock andtheir consecutive complications and disorders associated therewith.

Inflammatory diseases like rheumatoid arthritis, inflammatory lungdiseases like COPD, inflammatory bowel disease and psoriasis afflict onein three people in the course of their lives. Not only do those diseasesimpose immense health care costs, but also they are often crippling anddebilitating.

Although inflammation is the unifying pathogenic process of theseinflammatory diseases below, the current treatment approach is complexand is generally specific for any one disease. Many of the currenttherapies available today only treat the symptoms of the disease and notthe underlying cause of inflammation.

The compositions of the present invention are useful for the treatmentand/or prophylaxis of inflammatory diseases and consecutivecomplications and disorders. such as chronic or acute inflammation,inflammation of the joints such as chronic inflammatory arthritis,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenilerheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis,rubella arthritis, acute synovitis and gouty arthritis; inflammatoryskin diseases such as sunburn, psoriasis, erythrodermic psoriasis,pustular psoriasis, eczema, dermatitis, acute or chronic graftformation, atopic dermatitis, contact dermatitis, urticaria andscleroderma; inflammation of the gastrointestinal tract such asinflammatory bowel disease, Crohn's disease and related conditions,ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis,salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupuserythematosus and related disorders, multiple sclerosis, asthma,meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis,thrombophlebitis, respiratory diseases such as asthma, bronchitis,chronic obstructive pulmonary disease (COPD), inflammatory lung diseaseand adult respiratory distress syndrome, and allergic rhinitis;endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis,rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valvedisease, rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis.oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Moreover, cytokines are also believed to be implicated in the productionand development of various cardiovascular and cerebrovascular disorderssuch as congestive heart disease, myocardial infarction, the formationof atherosclerotic plaques, hypertension, platelet aggregation, angina,stroke, Alzheimer's disease, reperfusion injury, vascular injuryincluding restenosis and peripheral vascular disease, and, for example,various disorders of bone metabolism such as osteoporosis (includingsenile and postmenopausal osteoporosis), Paget's disease, bonemetastases, hypercalcaemia, hyperparathyroidism, osteosclerosis,osteoporosis and periodontitis, and the abnormal changes in bonemetabolism which may accompany rheumatoid arthritis and osteoarthritis.

Excessive cytokine production has also been implicated in mediatingcertain complications of bacterial, fungal and/or viral infections suchas endotoxic shock, septic shock and toxic shock syndrome and inmediating certain complications of CNS surgery or injury such asneurotrauma and ischaemic stroke.

Excessive cytokine production has, moreover, been implicated inmediating or exacerbating the development of diseases involvingcartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renalfibrosis, the cachexia found in certain chronic diseases such asmalignant disease and acquired immune deficiency syndrome (AIDS), tumourinvasiveness and tumour metastasis and multiple sclerosis. The treatmentand/or prophylaxis of these diseases are also contemplated by thepresent invention.

Additionally, the inventive compositions may be used to treatinflammation associated with autoimmune diseases including, but notlimited to, systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),glomerulonephritis, rheumatoid arthritis scleroderma, chronicthyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmunehemolytic anemia, glomerulonephritis, rheumatoid arthritis autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, and graft vs.host disease.

In a further embodiment the compositions of the present invention may beused for the treatment and prevention of infectious diseases such assepsis, septic shock, Shigellosis, and Helicobacter pylori and viraldiseases including herpes simplex type 1 (HSV-1), herpes simplex type 2(HSV-2), cytomegalovirus, Epstein-Barr, human immunodeficiency virus(HIV), acute hepatitis infection (including hepatitis A, hepatits B, andhepatitis C), HIV infection and CMV retinitis, AIDS or malignancy,malaria, mycobacterial infection and meningitis. These also includeviral infections, by influenza virus, varicella-zoster virus (VZV),Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7(HHV-7), human herpesvirus-8 (HHV-8), Poxvirus, Vacciniavirus,Monkeypoxvirus, pseudorabies and rhinotracheitis.

The compositions of the present invention may also be used topically inthe treatment or prophylaxis of topical disease states mediated by orexacerbated by excessive cytokine production, such as inflamed joints,eczema, psoriasis and other inflammatory skin conditions such assunburn; inflammatory eye conditions including conjunctivitis; pyresis,pain and other conditions associated with inflammation.

Periodontal disease has also been implemented in cytokine production,both topically and systemically. Hence, use of compositions of thepresent invention to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Finally, the compositions of the present invention may also be used totreat or prevent neurodegenerative disease selected from Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, frontotemporal lobar dementia, spinocerebellarataxia, dementia with Lewy bodies, cerebral ischemia orneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity or hypoxia.

In a preferred embodiment the compositions of the present invention maybe used to treat or prevent a disease selected from chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

Protein kinases are important enzymes involved in the regulation of manycellular functions. The LK6-serine/threonine-kinase gene of Drosophilamelanogaster was described as a short-lived kinase which can associatewith microtubules (J. Cell Sci. 1997, 110(2): 209-219). Genetic analysisin the development of the compound eye of Drosophila suggested a role inthe modulation of the RAS signal pathway (Genetics 2000 156(3):1219-1230). The closest human homologues of Drosophila LK6-kinase arethe MAP-kinase interacting kinase 2 (MNK2, e.g. the variants MNK2a andMNK2b) and MAP-kinase interacting kinase 1 (MNK1) and variants thereof.These kinases are mostly localized in the cytoplasm. MNKs arephosphorylated by the p42 MAP kinases Erk1 and Erk2 and the p38-MAPkinases. This phosphorylation is triggered in a response to growthfactors, phorbol esters and oncogenes such as Ras and Mos, and by stresssignaling molecules and cytokines. The phosphorylation of MNK proteinsstimulates their kinase activity towards eukaryotic initiation factor 4E(elF4E) (EMBO J. 16: 1909-1920, 1997; Mol Cell Biol 19, 1871-1880, 1990;Mol Cell Biol 21, 743-754, 2001). Simultaneous disruption of both, theMNK1 and MNK2 gene in mice diminishes basal and stimulated elF4Ephosphorylation (Mol Cell Biol 24, 6539-6549, 2004). Phosphorylation ofelF4E results in a regulation of the protein translation (Mol Cell Biol22: 5500-5511, 2001).

There are different hypotheses describing the mode of the stimulation ofthe protein translation by MNK proteins. Most publications describe apositive stimulatory effect on the cap-dependent protein translationupon activation of MAP kinase-interacting kinases. Thus, the activationof MNK proteins can lead to an indirect stimulation or regulation of theprotein translation, e.g. by the effect on the cytosolic phospholipase 2alpha (BBA 1488:124-138, 2000).

WO 03/037362 discloses a link between human MNK genes, particularly thevariants of the human MNK2 genes, and diseases which are associated withthe regulation of body weight or thermogenesis. It is postulated thathuman MNK genes, particularly the MNK2 variants are involved in diseasessuch as e.g. metabolic diseases including obesity, eating disorders,cachexia, diabetes mellitus, hypertension, coronary heart disease,hypercholesterolemia, dyslipidemia, osteoarthritis, biliary stones,cancer of the genitals and sleep apnea, and in diseases connected withthe ROS defense, such as e.g. diabetes mellitus and cancer. WO 03/03762moreover discloses the use of nucleic acid sequences of the MAPkinase-interacting kinase (MNK) gene family and amino acid sequencesencoding these and the use of these sequences or of effectors of MNKnucleic acids or polypeptides, particularly MNK inhibitors andactivators in the diagnosis, prophylaxis or therapy of diseasesassociated with the regulation of body weight or thermogenesis.

WO 02/103361 describes the use of kinases 2a and 2b (MNK2a and MNK2b)interacting with the human MAP kinase in assays for the identificationof pharmacologically active ingredients, particularly useful for thetreatment of diabetes mellitus type 2. Moreover, WO 02/103361 disclosesalso the prophylaxis and/or therapy of diseases associated with insulinresistance, by modulation of the expression or the activity of MNK2a orMNK2b. Apart from peptides, peptidomimetics, amino acids, amino acidanalogues, polynucleotides, polynucleotide analogues, nucleotides andnucleotide analogues, 4-hydroxybenzoic acid methyl ester are describedas a substance which binds the human MNK2 protein.

First evidence for a role of MNKs in inflammation was provided bystudies demonstrating activation of MNK1 by proinflammatory stimuli. Thecytokines TNFα and IL-1β trigger the activation of MNK1 in vitro(Fukunaga and Hunter, EMBO J 16(8): 1921-1933, 1997) and induce thephosphorylation of the MNK-specific substrate elF4E in vivo (Ueda etal., Mol Cell Biol 24(15): 6539-6549, 2004). In addition, administrationof lipopolysaccharide (LPS), a potent stimulant of the inflammatoryresponse, induces activation of MNK1 and MNK2 in mice, concomitant witha phosphorylation of their substrate elF4E (Ueda et al., Mol Cell Biol24(15): 6539-6549, 2004).

Furthermore, MNK1 has been shown to be involved in regulating theproduction of proinflammatory cytokines. MNK1 enhances expression of thechemokine RANTES (Nikolcheva et al., J Clin Invest 110, 119-126, 2002).RANTES is a potent chemo-tractant of monocytes, eosinophils, basophilesand, natural killer cells. It activates and induces proliferation of Tlymphocytes, mediates degranulation of basophils and induces therespiratory burst in eosinophils (Conti and DiGioacchino, Allergy AsthmaProc 22(3):133-7, 2001).

WO 2005/00385 and Buxade et al., Immunity 23: 177-189, August 2005 bothdisclose a link between MNKs and the control of TNFα biosynthesis. Theproposed mechanism is mediated by a regulatory AU-rich element (ARE) inthe TNFα mRNA. Buxade et al. demonstrate proteins binding andcontrolling ARE function to be phosphorylated by MNK1 and MNK2.Specifically MNK-mediated phosphorylation of the ARE-binding proteinhnRNP A1 has been suggested to enhance translation of the TNFα mRNA.

TNFα is not the only cytokine regulated by an ARE. Functional AREs arealso found in the transcripts of several interleukins, interferones andchemokines (Khabar, J Interf Cytokine Res 25: 1-10, 2005). TheMNK-mediated phosphorylation of ARE-binding proteins has thus thepotential to control biosynthesis of cytokines in addition to that ofTNFα.

Current evidence demonstrates MNKs as down stream targets ofinflammatory signalling as well as mediators of the inflammatoryresponse. Their involvement in the production of TNFα, RANTES, andpotentially additional cytokines suggests inhibition of MNKs as strategyfor anti-inflammatory therapeutic intervention.

MNK1 and MNK2 (including all splice forms) phosphorylate the translationfactor elF4E on Serine 209. MNK1/2 double knockout mice completely lackphosphorylation on Serine 209, indicating that MNK kinase are the onlykinases able to phosphorylate this site in vivo (Ueda et al., Mol CellBiol. 2004; 24(15):6539-49). elF4E is overexpressed in a wide range ofhuman malignancies, and high elF4E expression is frequently associatedwith more aggressive disease and poor prognosis. Furthermore, elF4E canact as an oncogene when assayed in standard assays for oncogenicactivity (e.g. Ruggero et al., Nat Med. 2004 May; 10(5):484-6). elF4Eexcerts its oncogenic activity by stimulating the translation ofoncogenes such as c-myc and cyclinD1 (Culjkovic et al., J Cell Biol.2006; 175(3):415-26), by increasing the expression of pro-survivalfactors such as MCP-1 (Wendel et al., Genes Dev. 2007; 21(24):3232-7)and by positively regulating pathways of drug resistance (Wendel et al.,Nature 2004; 428(6980):332-7; Graff et el., Cancer Res. 2008;68(3):631-4; De Benedetti and Graff, Oncogene 2004; 23(18):3189-99;Barnhart and Simon, J Clin Invest. 2007; 117(9):2385-8). Suppression ofelF4E expression by antisense oligonucleotides has shown promise inpreclinical experiments with human tumor cells (Graff et al., J ClinInvest. 2007; 117(9):2638-48). It has been shown that phosphorylation onSer209 is strictly required for the oncogenic activity of elF4E in vitroand in vivo (Topisirovic et al., Cancer Res. 2004; 64(23):8639-42;Wendel et al., Genes Dev. 2007; 21(24):3232-7). Thus, inhibition of MNK1and MNK2 is expected to have beneficial effects in human malignancies.

Inhibitors of MNK (referred to as CGP57380 and CGP052088) have beendescribed (cf. Mol. Cell. Biol. 21, 5500, 2001; Mol Cell Biol Res Comm3, 205, 2000; Genomics 69, 63, 2000). CGP052088 is a staurosporinederivative having an IC₅₀ of 70 nM for inhibition of in vitro kinaseactivity of MNK1. CGP57380 is a low molecular weight selective,non-cytotoxic inhibitor of MNK2 (MNK2a or MNK2b) or of MNK1: Theaddition of CGP57380 to cell culture cells, transfected with MNK2 (MNK2aor MNK2b) or MNK1 showed a strong reduction of phosphorylated elF4E.

WO 2007/147874 describes pyridine and pyrazine derivatives as MNK kinaseinhibitors. WO 2007/104053 describes 8-heteroarylpurines as MNK2inhibitors WO 2006/066937 discloses pyrazolopyrimidine compounds, and WO2006/136402 discloses certain thienopyrimidine compounds, both useful asMNK inhibitors.

DE 10 2007 024 470 and WO 2008/141843 disclose sulfoximine-substitutedquinoline and/or quinazoline derivatives which are claimed to act aserythropoietin-producing hepatoma amplified sequence-receptor kinaseinhibitors.

Aim of the Present Invention

The aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare MNK1 and/or MNK2 inhibitors.

Another aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichare potent and selective MNK1 and/or MNK2 inhibitors.

A further aim of the present invention is to provide new compounds, inparticular new sulfoximine substituted quinazoline derivatives, whichhave an inhibiting effect on the kinase activity of MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variants thereof in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further aim of the present invention is to provide effective MNK1and/or MNK2 inhibitors, in particular for the treatment of metabolicdisorders, for example metabolic diseases, inflammatory diseases,cancer, neurodegenerative diseases and their consecutive complicationand disorders.

Still a further aim of the present invention is to provide effectiveMNK1 and/or MNK2 inhibitors, in particular for the treatment ofmetabolic disorders, for example diabetes, dyslipidemia and/or obesityand their consecutive complication and disorders.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of the kinaseactivity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/orvariants thereof in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of new compounds, in particular sulfoximine substitutedquinazoline derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

Object of the Invention

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, in particular as MNK1 and/or MNK2 inhibitors.

The present invention concerns compounds of the general formula I:

wherein

Ar is selected from the group Ar-G1 consisting of:

-   -   wherein X is CH or N;    -   Y is S, O or NH;    -   R³ is H, halogen, CN or —C(═O)—NH₂; and    -   R⁴ is selected from the group R⁴-G1 consisting of:    -   a) C₃₋₇-cycloalkyl or C₃₋₇-cycloalkenyl,        -   each of which is optionally substituted with one to three            substituents independently selected from the group            consisting of halogen, CN, OH, CF₃, NH₂, —NH(C₁₋₃-alkyl),            —N(C₁₋₃-alkyl)₂, —NH—C(═O)—(C₁₋₃-alkyl),            —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—(C₁₋₃-alkyl), C₁₋₃-alkyl            optionally be substituted with 1 to 3 fluorine atoms,            C₃₋₇-cycloalkyl, —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl),            —O—(C₁₋₃-alkyl) optionally be substituted with 1 to 3            fluorine atoms, —COOH, —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂,            —C(═O)—NH(C₁₋₃-alkyl) and —C(═O)—N(C₁₋₃-alkyl)₂;    -   b) C₄₋₇-cycloalkyl optionally substituted with C₁₋₃-alkyl,        wherein in the cylcoalkyl moiety, one or two methylene groups        are replaced with a group independently selected from —C(═O)—,        O, S, SO, SO₂ or NR⁷,        -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—NH—(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂,            —SO₂—(C₁₋₃-alkyl), —SO₂—NH—(C₁₋₃-alkyl), —SO₂—N(C₁₋₃-alkyl)₂            or        -   C₁₋₅-alkyl optionally substituted with one to three F and/or            one CN, OH or heterocyclyl; and    -   c) a bicycle selected from:

-   -   -   wherein        -   Z₁, Z₂ and Z₃ are independently selected from among O and            CR⁸R⁹, with the proviso that either Z₁, Z₂ and Z₃ are all            CR⁸R⁹ or that one of Z₁, Z₂ and Z₃ is O and the remaining            Z₁-Z₃ are CR⁸R⁹,            -   wherein R⁸ is H, halogen, OH, CN or —O—(C₁₋₃-alkyl); and            -   R⁹ is H or C₁₋₃-alkyl; and        -   wherein one of X₁, X₂, X₃ and X₄ is N and the other three of            X₁, X₂, X₃ and X₄ are CH;            R¹ is selected from the group R¹-G1 consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, —O-heterocyclyl,            C₃₋₇-cycloalkyl, heterocyclyl or phenyl, wherein each alkyl            group is optionally substituted with one or more F; and        -   b) C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl,            heterocyclyl, heteroaryl, and aryl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F,    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —O(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with halogen, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocylcyl, heteroaryl,        —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,        —C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl),        —SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl); and

R² is selected from the group R²-G1 consisting of halogen, CN, OH, NH₂,C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl, azetidinyl,oxetanyl, —O—C₁₋₃-alkyl, —O-cyclopropyl, —O-azetidinyl, —S—C₁₋₃-alkyl,—S-cyclopropyl or —S-azetidinyl, wherein each alkyl group is optionallysubstituted with one or more F; and

wherein, if not otherwise specified, each alkyl group in the abovedefinitions may be substituted with one to three F;

including any tautomers and stereoisomers thereof,

or a salt thereof

or a solvate or hydrate thereof.

If not specified otherwise, any alkyl moiety mentioned in thisapplication may be straight-chained or branched and may be substitutedwith one to three F.

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are influenced by the inhibition of thekinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)and/or variants thereof in a patient in need thereof characterized inthat a compound of general formula I or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition influenced by the inhibition of the kinase activityof MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) and/or variantsthereof in a patient that includes the step of administering to thepatient in need of such treatment a therapeutically effective amount ofa compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are influenced by theinhibition of the kinase activity of MNK1 (MNK1a or MNK1b) and/or MNK2(MNK2a or MNK2b) and/or variants thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the groups, residues and substituents,particularly Ar, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, Z₁, Z₂, Z₃, X₁, X₂, X₃and X₄ are defined as above and hereinafter. If residues, substituents,or groups occur several times in a compound, they may have the same ordifferent meanings. Some preferred meanings of individual groups andsubstituents of the compounds according to the invention will be givenhereinafter. Any and each of these definitions may be combined with eachother.

Ar:

Ar-G1:

According to one embodiment, the group Ar is selected from the groupAr-G1 as defined hereinbefore and hereinafter.

Ar-G1a:

According to another embodiment, the group Ar is selected from the groupAr-G1a consisting of:

wherein X is CH or N;Y is S, O or NH;R³ is H, halogen, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G2:

According to another embodiment, the group Ar is selected from the groupAr-G2 consisting of:

wherein X is CH or N;R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.Ar-G2a:

According to another embodiment, the group Ar is selected from the groupAr-G2a consisting of:

wherein R⁴ is as defined hereinbefore or hereinafter.Ar-G2b:

According to another embodiment, the group Ar is selected from the groupAr-G2b consisting of:

wherein R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; andR⁴ is as defined hereinbefore or hereinafter.

Preferably, R³ is F.

Ar-G3:

According to another embodiment, the group Ar is selected from the groupAr-G3 consisting of:

wherein Y is S, O or NH; andR⁴ is as defined hereinbefore or hereinafter.Ar-G3a:

According to another embodiment, the group Ar is selected from the groupAr-G3a consisting of:

R⁴ is as defined hereinbefore or hereinafter.

Preferably, R⁴ is tetrahydrofuran-3-yl.

R⁴:

R⁴-G1:

According to one embodiment, the group R⁴ is selected from the groupR⁴-G1 as defined hereinbefore and hereinafter.

R⁴-G1a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G1a consisting of:

-   -   a) C₃₋₇-cycloalkyl or C₃₋₇-cycloalkenyl,        -   each of which is optionally substituted with one to three            substituents independently selected from the group            consisting of halogen, CN, OH, CF₃, NH₂,            —NH—C(═O)—(C₁₋₃-alkyl), —NH—C(═O)—O—(C₁₋₄-alkyl),            —NH—SO₂—(C₁₋₃-alkyl), C₁₋₃-alkyl optionally be substituted            with 1 to 3 fluorine atoms, C₃₋₇-cycloalkyl,            —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl), —O—(C₁₋₃-alkyl)            optionally be substituted with 1 to 3 fluorine atoms, —COOH,            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) and            —O(═O)—N(C₁₋₃-alkyl)₂;    -   b) C₄₋₇-cycloalkyl optionally substituted with C₁₋₃-alkyl,        wherein in the cylcoalkyl moiety, one or two methylene groups        are replaced with a group independently selected from —C(═O)—,        O, S, SO, SO₂ or NR⁷,        -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—NH—(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂,            —SO₂—(C₁₋₃-alkyl), —SO₂—NH—(C₁₋₃-alkyl), —SO₂—N(C₁₋₃-alkyl)₂            or        -   C₁₋₅-alkyl optionally substituted with one to three F and/or            one CN, OH or heterocyclyl; and    -   c) a bicycle selected from:

-   -   -   wherein        -   Z₁, Z₂ and Z₃ are independently selected from among O and            CR⁸R⁹, with the proviso that either Z₁, Z₂ and Z₃ are all            CR⁸R⁹ or that one of Z₁, Z₂ and Z₃ is O and the remaining            Z₁-Z₃ are CR⁸R⁹,            -   wherein R⁸ is H, halogen, OH, CN or —O—(C₁₋₃-alkyl); and            -   R⁹ is H or C₁₋₃-alkyl; and        -   wherein one of X₁, X₂, X₃ and X₄ is N and the other three of            X₁, X₂, X₃ and X₄ are CH;            R⁴-G2:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G2 consisting of:

-   -   a) C₃₋₇-cycloalkyl, which is optionally substituted with one or        two substituents independently selected from the group        consisting of F, Cl, CN, OH, CF₃, NH₂, —NH(C₁₋₃-alkyl),        —N(C₁₋₃-alkyl)₂, —NH—C(═O)—CH₃, —NH—C(═O)—O—(C₁₋₄-alkyl),        —NH—SO₂—(C₁₋₃-alkyl), C₁₋₃-alkyl optionally substituted with 1        to 3 fluorine atoms, —O—(C₁₋₃-alkyl) optionally substituted with        1 to 3 fluorine atoms, —COOH, —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂,        —C(═O)—NH(C₁₋₃-alkyl) and —O(═O)—N(C₁₋₃-alkyl)₂;    -   b) C₄₋₇-cycloalkyl optionally substituted with C₁₋₃-alkyl,        wherein in the cylcoalkyl moiety, one or two methylene groups        are replaced with a group independently selected from —C(═O)—,        O, S, or NR⁷,    -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—(C₁₋₃-alkyl) or    -   C₁₋₅-alkyl optionally substituted with one to three F and/or one        CN, OH or oxadiazolyl; and    -   c) a bicycle selected from:

-   -   wherein    -   Z₁, Z₂ and Z₃ are independently selected from among O and CR⁸R⁹,        with the proviso that either Z₁, Z₂ and Z₃ are all CR⁸R⁹ or that        one of Z₁, Z₂ and Z₃ is O and the remaining Z₁-Z₃ are CR⁸R⁹,    -   wherein R⁸ is H, halogen, OH, CN or —O—(C₁₋₃-alkyl); and    -   R⁹ is H or C₁₋₃-alkyl; and    -   wherein one of X₁, X₂, X₃ and X₄ is N and the other three of X₁,        X₂, X₃ and X₄ are CH.        R⁴-G3:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G3 consisting of:

-   -   a) C₃₋₆-cycloalkyl, which is optionally substituted with one F,        CN, OH, CH₃, CF₃, NH₂, —NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂,        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃, C₁₋₃-alkyl,        —O—(C₁₋₃-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) or        —C(═O)—N(C₁₋₃-alkyl)₂ and may additionally be substituted with        one F or CH₃;    -   b) C₅₋₇-cycloalkyl optionally substituted with one CH₃, wherein        in the cylcoalkyl moiety, one methylene group is replaced with        O, S, or NR⁷ and a second methylene group may be replaced with O        or —C(═O)—,    -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ or C₁₋₄-alkyl        optionally substituted with one to three F and/or one CN, OH or        oxadiazolyl; and    -   c) a bicycle selected from:

-   -   wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and    -   R⁹ is H or CH₃.        R⁴-G4:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G4 consisting of:

R⁴-G5a:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5a consisting of:

R⁴-G5b:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G5b consisting of:

R⁴-G6:

According to another embodiment, the group R⁴ is selected from the groupR⁴-G6 consisting of:

R¹:R¹-G1:

According to one embodiment, the group R¹ is selected from the groupR¹-G1 as defined hereinbefore and hereinafter.

R¹-G1a:

According to another embodiment, the group R¹ is selected from the groupR¹-G1a consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₃-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, —O-heterocyclyl,            C₃₋₇-cycloalkyl, heterocyclyl or phenyl, wherein each alkyl            group is optionally substituted with one or more F; and        -   b) C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl, heteroaryl,            and aryl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F,    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with halogen, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocylcyl, heteroaryl,        —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,        —C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl),        —SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl).        R¹-G2:

According to another embodiment, the group R¹ is selected from the groupR¹-G2 consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, or            phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₃₋₇-cycloalkyl, tetrahydropyranyl, pyridinyl, and            phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with F, Cl, Br, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, piperidinyl, piperazinyl,        morpholinyl, pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl,        pyrazinyl, pyridazinyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl),        —C(═O)—N(C₁₋₄-alkyl)₂, —COOH, —C(═O)—O—(C₁₋₄-alkyl),        —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl), —SO—(C₁₋₄-alkyl) or        —SO₂—(C₁₋₄-alkyl).

Preferably, R¹ is selected from the group consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, or            phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₃₋₇-cycloalkyl, tetrahydropyranyl, pyridinyl, and            phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —O(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl).            R¹-G3:

According to another embodiment, the group R¹ is selected from the groupR¹-G3 consisting of:

-   -   wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,        cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl,        -   wherein the alkyl group is optionally substituted with            —O—(C₁₋₃-alkyl) or phenyl; and    -   R⁶ is C₁₋₃-alkyl;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        further to the sulfur atom may contain one O, S or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃.            R¹-G3a:

According to another embodiment, the group R¹ is selected from the groupR¹-G3a consisting of:

-   -   wherein R⁵ is C₁₋₄-alkyl, cyclopropyl, tetrahydropyranyl,        pyridinyl or phenyl,        -   wherein the alkyl group is optionally substituted with            —O—CH₃ or phenyl; and    -   R⁶ is methyl or ethyl.        R¹-G3b:

According to another embodiment, the group R¹ is selected from the groupR¹-G3b consisting of:

-   -   wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        further to the sulfur atom may contain one O or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃.            R¹-G4:

According to another embodiment, the group R¹ is selected from the groupR¹-G4 consisting of:

R¹-G5a:

According to another embodiment, the group R¹ is selected from the groupR¹-G5a consisting of:

Preferably, the group R¹ is selected from the group consisting of:

R¹-G5b:

According to another embodiment, the group R¹ is selected from the groupR¹-G5b consisting of:

R²:R²-G1:

According to one embodiment, the group R² is selected from the groupR²-G1 as defined hereinbefore and hereinafter.

R²-G2:

According to another embodiment, the group R² is selected from the groupR²-G2 consisting of F, Cl, Br, CN, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₂₋₃-alkenyl, —O—C₁₋₃-alkyl and —S—C₁₋₃-alkyl, wherein each alkyl groupis optionally substituted with one or more F.

R²-G3:

According to another embodiment, the group R² is selected from the groupR²-G3 consisting of F, Cl, Br, C₁₋₂-alkyl, cyclopropyl, —CH═CH₂ and—O—C₁₋₂-alkyl, wherein each alkyl group is optionally substituted withone to three F.

R²-G4:

According to another embodiment, the group R² is selected from the groupR²-G4 consisting of F, Cl, Br, CH₃, CHF₂ and —O—CH₃.

R²-G5:

According to another embodiment, the group R² is selected from the groupR²-G5 consisting of CH₃.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.5, wherein any tautomers andstereoisomers, solvates, hydrates and salts thereof, in particular thepharmaceutically acceptable salts thereof, are encompassed.

wherein the variables R¹, R², R³, R⁴ and X are defined as hereinbeforeand hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodi- ment Ar R¹ R² X R⁴ E-1 Ar-G1 R¹-G1 R²-G1 CH or N R⁴-G1 E-2 Ar-G2R¹-G2 R²-G2 CH or N R⁴-G2 E-3 Ar-G2 R¹-G3 R²-G3 CH or N R⁴-G3 E-4 Ar-G2R¹-G3a R²-G3 CH or N R⁴-G3 E-5 Ar-G2 R¹-G3b R²-G3 CH or N R⁴-G3 E-6Ar-G2 R¹-G4 R²-G4 CH or N R⁴-G4 E-7 Ar-G2 R¹-G5 R²-G4 CH or N R⁴-G3 E-8Ar-G2 R¹-G4 R²-G4 CH or N R⁴-G5 E-9 Ar-G2 R¹-G4 R²-G4 CH or N R¹-G6 E-10Ar-G2a R¹-G5a F, Cl, CH₃ — R⁴-G5b E-11 Ar-G2a R¹-G5a CH₃ — R⁴-G5b E-12Ar-G2a

F, Cl, CH₃ — R⁴-G5b E-13 Ar-G2b R¹-G3 R²-G3 — R⁴-G3 E-14 Ar-G2b R¹-G3R²-G4 — R⁴-G3 E-15 Ar-G2b R¹-G3a R²-G4 — R⁴-G3 E-16 Ar-G2b R¹-G3b R²-G4— R⁴-G3 E-17 Ar-G2b R¹-G4 R²-G4 — R⁴-G3 E-18 Ar-G2b R¹-G5b R²-G4 — R⁴-G3E-19 Ar-G2b R¹-G3 R²-G4 — R⁴-G5a E-20 Ar-G2b R¹-G3 R²-G4 — R⁴-G6 E-21Ar-G2b; R¹-G3 R²-G3 — R⁴-G3 R³ = F E-22 Ar-G2b; R¹-G3 R²-G4 — R⁴-G3 R³ =F E-23 Ar-G2b; R¹-G3a R²-G4 — R⁴-G3 R³ = F E-24 Ar-G2b; R¹-G3b R²-G4 —R⁴-G3 R³ = F E-25 Ar-G2b; R¹-G4 R²-G4 — R⁴-G3 R³ = F E-26 Ar-G2b; R¹-G5bR²-G4 — R⁴-G3 R³ = F E-27 Ar-G2b; R¹-G3 R²-G4 — R⁴-G5a R³ = F E-28Ar-G2b; R¹-G3 R²-G4 — R⁴-G6 R³ = F

Another embodiment concerns those compounds of formula I, wherein

Ar is selected from the group Ar-G2 consisting of:

-   -   wherein X is CH or N;    -   R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; and    -   R⁴ is selected from a group consisting of:    -   a) C₃₋₆-cycloalkyl, which is optionally substituted with one F,        CN, OH, CH₃, CF₃, NH₂, —NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂,        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃, C₁₋₃-alkyl,        —O—(C₁₋₃-alkyl) or —C(═O)—NH₂, and may additionally be        substituted with one F or CH₃;    -   b) C₅₋₇-cycloalkyl optionally substituted with one CH₃, wherein        in the cylcoalkyl moiety, one methylene group is replaced with        O, S, or NR⁷ and a second methylene group may be replaced with O        or —C(═O)—,    -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ or C₁₋₄-alkyl        optionally substituted with one to three F and/or one CN, OH or        oxadiazolyl; and    -   c) a bicycle selected from:

-   -   wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and    -   R⁹ is H or CH₃;

R¹ is selected from the group R¹-G3 consisting of:

-   -   wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,        cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl,        -   wherein the alkyl group is optionally substituted with            —O—(C₁₋₃-alkyl) or phenyl; and    -   R⁶ is C₁₋₃-alkyl;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        further to the sulfur atom may contain one O, S or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃; and

R² is selected from the group R²-G3 consisting of F, Cl, Br, C₁₋₂-alkyl,cyclopropyl, —CH═CH₂ and —O—C₁₋₂-alkyl, wherein each alkyl group isoptionally substituted with one to three F;

and the pharmaceutically acceptable salts thereof.

Another embodiment concerns those compounds of formula I, wherein

Ar is selected from the group Ar-G2a consisting of:

-   -   wherein R⁴ is selected from the group R⁴-G5b consisting of:

R¹ is selected from the group R¹-G5a consisting of:

preferably R¹ is

and

R² is F, C₁ or CH₃; preferably R² is F or CH₃; more preferably, R² isCH₃;

and the pharmaceutically acceptable salts thereof.

Another embodiment concerns those compounds of formula I, wherein

Ar is selected from the group Ar-G2b consisting of:

-   -   wherein R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; preferably, R³ is        F; and    -   R⁴ is selected from a group consisting of:    -   a) C₃₋₆-cycloalkyl, which is optionally substituted with one F,        CN, OH, CH₃, CF₃, NH₂, —NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂,        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃, C₁₋₃-alkyl,        —O—(C₁₋₃-alkyl) or —C(═O)—NH₂, and may additionally be        substituted with one F or CH₃;    -   b) C₅₋₇-cycloalkyl optionally substituted with one CH₃, wherein        in the cylcoalkyl moiety, one methylene group is replaced with        O, S, or NR⁷ and a second methylene group may be replaced with O        or —C(═O)—,    -   wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ or C₁₋₄-alkyl        optionally substituted with one to three F and/or one CN, OH or        oxadiazolyl; and    -   c) a bicycle selected from:

-   -   wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and    -   R⁹ is H or CH₃;

R¹ is selected from the group R¹-G3 consisting of:

-   -   wherein R⁵ is selected from the group consisting of C₁₋₃-alkyl,        cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl,        -   wherein the alkyl group is optionally substituted with            —O—(C₁₋₃-alkyl) or phenyl; and    -   R⁶ is C₁₋₃-alkyl;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 6-membered saturated heterocycle that        further to the sulfur atom may contain one O, S or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),            —C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃; and            R² is selected from the group R²-G3 consisting of F, Cl, Br,            C₁₋₂-alkyl, cyclopropyl, —CH═CH₂ and —O—C₁₋₂-alkyl, wherein            each alkyl group is optionally substituted with one to three            F;            preferably, R² is selected from the group R²-G4 consisting            of F, Cl, CH₃, and —O—CH₃;            and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

Another embodiment of the invention concerns compounds of formula

wherein

R¹ is selected from the group consisting of H, halogen, and a group offormula

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, —O-heterocyclyl,            C₃₋₇-cycloalkyl, heterocyclyl or phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl,            heterocyclyl, heteroaryl, and aryl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F,    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl);    -   and wherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶        together with the sulfur atom to which they are attached may        each be independently substituted with halogen, CN, OH, NH₂,        —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl),        —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,        —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,        —N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—NH₂,        —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),        —N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl),        C₁₋₆-alkyl, C₃₋₇-cycloalkyl, heterocylcyl, heteroaryl,        —C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,        —C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl);        —SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl);        R² is selected from the group R²-G1 consisting of halogen, CN,        OH, NH₂, C₁₋₃-alkyl, C₂₋₃-alkenyl, C₂₋₃-alkinyl,        C₃₋₇-cycloalkyl, azetidinyl, oxetanyl, —O—C₁₋₃-alkyl,        —O-cyclopropyl, —O-azetidinyl, —S—C₁₋₃-alkyl, —S-cyclopropyl or        —S-azetidinyl, wherein each alkyl group is optionally        substituted with one or more F; and        R′ are identical or different from each other and are each        C₁₋₄-alkyl,        or both R′groups are linked and together with the N atom to        which they are attached form a pyrrolidinyl, piperidinyl,        piperazinyl or morpholinyl ring;        wherein, if not otherwise specified, each alkyl group in the        above definitions may be substituted with one to three F;        including any tautomers and stereoisomers thereof,        or a salt thereof        or a solvate or hydrate thereof.

A preferred embodiment concerns those compounds of formula II, wherein

R¹ is selected from the group consisting of:

-   -   wherein R⁵ is selected from the group consisting of:        -   a) C₁₋₄-alkyl, which is optionally substituted with            —O—(C₁₋₃-alkyl), —O—C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl, or            phenyl,            -   wherein each alkyl group is optionally substituted with                one or more F; and        -   b) C₃₋₇-cycloalkyl, tetrahydropyranyl, pyridinyl, and            phenyl; and    -   R⁶ is C₁₋₃-alkyl which is optionally substituted with one or        more F;    -   or wherein R⁵ and R⁶ together with the sulfur atom to which they        are attached form a 4- to 7-membered saturated or partly        unsaturated heterocycle that further to the sulfur atom may        contain one O, S or NR^(N),        -   wherein said heterocycle is optionally substituted with OH            or —O—CH₃; and        -   wherein R^(N) is H, C₁₋₃-alkyl, —C(═O)—(C₁₋₃-alkyl),            —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl),            —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl):            R² is F, Cl, Br, C₁₋₃-alkyl, CF₃, —OCH₃ or cyclopropyl; and            each R′ is independently selected form methyl and ethyl;            or a salt thereof.

A more preferred embodiment concerns those compounds of formula II,wherein

R¹ is selected from the group consisting of:

-   -   wherein R⁵ is C₁₄₂-alkyl, cyclopropyl, tetrahydropyranyl,        pyridinyl or phenyl,        -   wherein the alkyl group is optionally substituted with            —O—CH₃ or phenyl; and    -   R⁶ is methyl or ethyl;        R² is F, Cl, Br, C₁₋₃-alkyl, CF₃, —OCH₃ or cyclopropyl; and        each R′ is methyl;        or a salt thereof.

Preferred examples for compounds of formula II are:

The compounds of formula (II) are useful as intermediates for thepreparation of the compounds of formula I.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to one skilled in the art but are not describedin detail here may also be used. The general processes for preparing thecompounds according to the invention will become apparent to a personskilled in the art on studying the schemes that follow. Startingcompounds are commercially available or may be prepared by methods thatare described in the literature or herein, or may be prepared in ananalogous or similar manner. Before the reaction is carried out anycorresponding functional groups in the compounds may be protected usingconventional protecting groups. These protecting groups may be cleavedagain at a suitable stage within the reaction sequence using methodsfamiliar to a person skilled in the art.

Typical methods of preparing the compounds of the invention aredescribed in the experimental section.

The potent inhibitory effect of the compounds of the invention can bedetermined by in vitro enzyme assays as described in the experimentalsection.

The compounds of the present invention may also be made by methods knownin the art including those described below and including variationswithin the skill of the art.

Compounds of the general formula 1-3, wherein X, R³ and R⁴ are aspreviously defined, can be prepared via the process outlined in Scheme 1using a compound of the general formula 1-1, wherein X and R³ are aspreviously defined, with an alcohol of the general formula 1-2, whereinR⁴ is as previously defined, in presence of a base in appropriatesolvents such as THF or DMF at a temperature between 0° C. and 150° C.As base sodium hydride or lithium hexamethyldisilazane may be used.Hydrogenation of a compound of the general formula 1-3, wherein X, R³and R⁴ are as previously defined, in order to obtain a compound of thegeneral formula 1-4, wherein X, R³ and R⁴ are as previously defined, maybe achieved in the presence of hydrogen and a catalyst such as palladiumor Raney nickel in an appropriate solvent. Hydrogen can be introduced asa gas or stem from a hydrogen source such as ammonium formate.

In Scheme 2 compounds of the general formula 2-3, wherein X, R³ and R⁴are as previously defined, may be obtained by Mitsunobu reaction of acompound with the general formula 2-1, wherein X, R³ are as previouslydefined, with an alcohol of the general formula 2-2, wherein R⁴ is aspreviously defined, in the presence of triphenylphosphine and andialkylazodicarboxylate such as diethylazodicarboxylate,diisopropylazodicarboxylate or di-tert.butylazodiacarboxylate in asolvent such as THF at temperatures between −10° C. and 80° C.,preferrably between 0° C. and 30° C.

4,5,7-substituted quinazolines of the general formula 3-4, wherein X,R¹, R², R³ and R⁴ are as previously defined, may be prepared as shown inscheme 3. Substituted antranilonitriles of the general formula 3-1,wherein R¹ and R² are as previously defined, may react withN,N-dimethylformamide dimethyl acetal under reflux. The resultingformamidines of the general formula 3-2, wherein R¹ and R² are aspreviously defined, may be condensed with primary aromatic amines of thegeneral formula 3-3, wherein X, R³ and R⁴ are as previously defined, inacetic acid (J. Med. Chem., 2010, 53 (7), 2892-2901). Dioxane can beused as cosolvent in this reaction.

The sulphoximine-substituent of the general formula 4-3, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 4 byPd or Cu-catalyzed coupling reactions from the corresponding boronicacid derivatives of the general formula 4-2, wherein R² is as previouslydefined.

The boronic esters of the general formula 4-2, wherein R² is aspreviously defined, may be prepared using a Ir-catalyzed boronylationreaction (Chem. Rev., 2010, 110 (2), 890-931) and coupled with thesulphoximine of the general formula 4-3, wherein R⁵ and R⁶ are aspreviously defined, under Cu-catalysis in a suitable solvent like MeOH(Org. Lett., 2005, 7(13), 2667-2669).

The sulphoximine-substituent of the general formula 5-2, wherein R⁵ andR⁶ are as previously defined, may be introduced as shown in Scheme 5 byPd or Cu-catalyzed coupling reactions from the corresponding bromoderivatives of the general formula 5-1 or 5-4, wherein Ar and R² are aspreviously defined.

For the palladium catalyzed coupling one of the following reactionconditions may be used Pd(OAc)₂, BINAP, Cs₂CO₃ in toluene as solvent (J.Org. Chem., 2000, 65 (1), 169-175), or Pd₂dba₃, 2-(di-t-butylphosphino)biphenyl, NaO^(t)Bu in dioxane or DMF as solvent (cf. WO 2008/141843A1).

In case the R²-substituent of compounds of the general formula 6-2 or6-4 in Scheme 6, wherein Ar, R², R⁵ and R⁶ are as previously defined, islinked via a nitrogen, oxygen or sulphur atom to the ring system, thecorresponding substituent R² may be introduced by nucleophilic aromaticsubstitution from the aryl flouride of the general formula 6-1 or 6-3,wherein Ar, R⁵ and R⁶ are as previously defined, using a suitable basein an inert solvent like Cs₂CO₃ in dioxane or NaH, LiHMDS or DIPEA inNMP.

As shown in Scheme 7 the sulphoximines of the general formula 7-2,wherein R⁵ and R⁶ are as previously defined, may be prepared from thecorresponding sulphoxides of the general formula 7-1, wherein R⁵ and R⁶are as previously defined, by reaction with sodium azide and sulfuricacid (H₂SO₄). A suitable solvent like dichloromethane maybe used.

Alternatively, sulfoximines of the general formula 7-2, wherein R⁵ andR⁶ are as previously defined, may be prepared from the correspondingsulphoxides of the general formula 7-1, wherein R⁵ and R⁶ are aspreviously defined, by reaction with o-mesitylenesulphonylhydroxylamine(MSH) in presence of a suitable solvent like dichlormethane.

As shown in scheme 8 sulphoxides of the general formula 8-1, wherein R⁵and R⁶ are as previously defined, may be react with trifluoracetamide inpresence of PhI(OAc)₂, Rh₂(OAc)₄, and MgO in a suitable solvent likedichlormethane to form compounds of the general formula 8-2, wherein R⁵and R⁶ are as previously defined.

Sulfoximines of the general formula 8-3, wherein R⁵ and R⁶ are aspreviously defined, may be prepared by samponification of compounds ofthe general formula 8-2, wherein R⁵ and R⁶ are as previously defined(Org. Lett., 2004, 6 (8), 1305-1307). Alternatively, other suitableprotecting groups and Iron as catalyst can be utilized (Org. Lett.,2006, 8 (11), 2349-2352).

In scheme 9 a general synthesis of sulfoximines of the general formula9-5, wherein R⁵ and R⁶ are as previously defined, is described.

Starting from the thioethers of the general formula 9-1, wherein R⁵ andR⁶ are as previously defined, the corresponding N-cyano sulfilimines ofthe general formula 9-2, wherein R⁵ and R⁶ are as previously defined,maybe prepared by reaction with cyanamide in the presence of a base likeNaO^(t)Bu or KO^(t)Bu and NBS or I₂ in a suitable solvent like methanol.The sulfilimines of the general formula 9-2, wherein R⁵ and R⁶ are aspreviously defined, are oxidized to the N-cyanosulfoximines of thegeneral formula 9-3, wherein R⁵ and R⁶ are as previously defined. Afterremoval of the N-cyano group the N-trifluoroacetylsulfoximines of thegeneral formula 9-4, wherein R⁵ and R⁶ are as previously defined, may beobtained. After removal of the trifluoroacetyl moiety the NH-freesulfoximines of the general formula 9-5, wherein R⁵ and R⁶ are aspreviously defined, can be obtained (Org. Lett., 2007, 9 (19),3809-3811).

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula I”, “compound(s) of the invention” and the like denote thecompounds of the formula I according to the present invention includingtheir tautomers, stereoisomers and mixtures thereof and the saltsthereof, in particular the pharmaceutically acceptable salts thereof,and the solvates and hydrates of such compounds, including the solvatesand hydrates of such tautomers, stereoisomers and salts thereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionof the particular disease or condition, (ii) attenuation, amelioration,or elimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex)” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo-, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking pharmaceutically acceptable acid or base salts thereof.

Salts of acids which are useful, for example, for purifying or isolatingthe compounds of the present invention are also part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example, the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer from 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight-chain or branched divalent alkyl radical containing from 1 to ncarbon atoms. For example, the term C₁₋₄-alkylene includes —(CH₂)—,—(CH₂—CH₂)—, —(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—(CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—(CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—(CH₂—CH₂)—, —(CH₂—CH(CH₃)—(CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—(C₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term “C₂₋₃” alkenylene includes—CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃—alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cycloalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cycloalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term bicyclic includes spirocyclic.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl and morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

-   -   R^(N)═H or residue attached via a C atom

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The biological activity of compounds was determined by the followingmethods:

A. MNK2a In Vitro Kinase Assay (Assay 1)

ASSAY SETUP: The inhibition of kinase activity of MNK2a was assessedusing preactivated GST-MNK2a. The white, 384-well OptiPlate F plateswere purchased from Perkin Elmer. The ADP-Glo Kinase Assay (includingultra pure ATP) was purchased from Promega (V9103). Activated MNK2a wasobtained as described in WO2011/104340. The unlabeled eIF4E peptide(NH2-TATKSGSTTKNR—CONH2) (SEQ ID NO: 1), differing from Seq. ID No. 5 ofWO 2011/104340 by the C-terminal —CONH2 group, was purchased from ThermoFisher Scientific. All other materials were of highest gradecommercially available. Compounds are tested in either serial dilutionsor single dose concentrations. The compound stock solutions are 10 mM in100% DMSO The serial compound dilutions are prepared in 100% DMSOfollowed by 1:27.3 intermediate dilution in assay buffer. The final DMSOconcentration in assay will be <3%. In the 384-well plates 3 μl of testcompound from the intermediate dilution is mixed with 4 μl of theactivated MNK2 enzyme (final concentration of 10 nM) and 4 μl of thepeptide (final concentration of 25 μM)/ultra pure ATP (finalconcentration of 20 μM), all dissolved in assay buffer. This step isfollowed by an incubation time of 90 min, then 10 μl of ADP Glo reagentare added, followed by 40 min of incubation. Then 20 μl of kinasedetection reagent are admixed. The plates are sealed and after anincubation period of 30 min, the luminescence signal is measured in anEnvision reader to determine the amount of produced ADP. All incubationsteps are performed at room temperature. The assay buffer consists of 20mM HEPES, 2 mM DTT, 0.01% BSA, 20 mM MgCl2 and 0.1% Pluronic F-127.

Each assay microtiter plate contains wells with vehicle controls insteadof compound (1% DMSO in water) as reference for the high signal (100%CTL, high signal), and wells containing a potent MNK2 inhibitor (final20 μM, 1% DMSO) as reference for low signal (0% CTL, low signal).

The luminescent signal generated is proportional to the ADPconcentration produced and is correlated with activated MNK2 activity.The analysis of the data is performed by the calculation of thepercentage of ATP consumption of activated MNK2 in the presence of thetest compound compared to the consumption of ATP in the presence ofactivated MNK2 without compound.(RLU(sample)−RLU(low control))*100/(RLU(high value)−RLU(low control))[RLU=relative luminescence units]

An inhibitor of the MNK2 enzyme will give values between 100% CTL (noinhibition) and 0% CTL (complete inhibition). Values of more than 100%CTL are normally related to compound/sample specific physico-chemicalproperties (e.g. solubility, light absorbance, fluorescence).

IC50 values based on dose response curves are calculated with theAssayExplorer software.

B. MNK1 In Vitro Kinase Assay (Assay 2)

MNK1 Data can be obtained from the MNK1 Z′-LYTE® assay. The MNK1Z′-LYTE® screening protocol and assay conditions are also described onwww.invitrogen.com.

The assay is described as follows:

The Z′-LYTE® biochemical assay employs a fluorescence-based,coupled-enzyme format and is based on the differential sensitivity ofphosphorylated and non-phosphorylated peptides to proteolytic cleavage.The peptide substrate is labeled with two fluorophores—one at eachend—that make up a FRET pair.

In the primary reaction, the kinase transfers the gamma-phosphate of ATPto a single tyrosine, serine or threonine residue in a syntheticFRET-peptide. In the secondary reaction, a site-specific proteaserecognizes and cleaves non-phosphorylated FRET-peptides. Phosphorylationof FRET-peptides suppresses cleavage by the Development Reagent.Cleavage disrupts FRET between the donor (i.e., coumarin) and acceptor(i.e., fluorescein) fluorophores on the FRET-peptide, whereas uncleaved,phosphorylated FRET-peptides maintain FRET. A ratiometric method, whichcalculates the ratio (the Emission Ratio) of donor emission to acceptoremission after excitation of the donor fluorophore at 400 nm, is used toquantitate reaction progress, as shown in the equation below.Emission Ratio=Coumarin Emission(445 nm)/Fluorescein Emission(520 nm)

ASSAY SETUP: The inhibition of kinase activity of MNK1a was assessedusing pre-activated GST-MNK1a. The 2×MKNK1 (MNK1) mixture is prepared in50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 4 mM MnCl₂, 1 mM EGTA, 2mM DTT. The final 10 μL Kinase Reaction consists of 13.5-54 ng MKNK1(MNK1) and 2 μM Ser/Thr 07 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl₂, 2 mM MnCl₂, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase Reactionincubation, 5 μL of a 1:32768 dilution of Development Reagent A isadded.

Assay Conditions

Test Compounds:

The Test Compounds are screened in 1% DMSO (final) in the well.

Peptide/Kinase Mixtures:

All Peptide/Kinase Mixtures are diluted to a 2× working concentration inthe MNK1 Kinase Buffer.

ATP Solution:

All ATP Solutions are diluted to a 4× working concentration in KinaseBuffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA).

Development Reagent Solution:

The Development Reagent is diluted in Development Buffer

Assay Protocol:

Bar-coded Corning, low volume NBS, 384-well plate (Corning Cat. #3676)

1. 2.5 μL-4× Test Compound

2. 5 μL-2× Peptide/Kinase Mixture

3. 2.5 μL-4×ATP Solution

4. 30-second plate shake

5. 60-minute Kinase Reaction incubation at room temperature

6. 5 μL-Development Reagent Solution

7. 30-second plate shake

8. 60-minute Development Reaction incubation at room temperature

9. Read on fluorescence plate reader and analyze the data

Data Analysis

The following equations are used for each set of data points:

Correction for Background Fluorescence: F_(Sample)−FI_(TCFl Ctl)

Emission Ratio (using values corrected for backgroundfluorescence):Coumarin

Emission (445 nm)/Fluorescein Emission (520 nm)

% Phosphorylation (% Phos):1−((Emission Ratio×F _(100%))−C _(100%))/((C _(0%) −C _(100%))+[EmissionRatio×(F _(100%) −F _(0%))])*100% Inhibition:1−(% Phos_(Sample)/% Phos_(0% Inhibition Ctl))*100FI=Fluorescence IntensityC_(100%)=Average Coumarin emission signal of the 100% Phos. ControlC_(0%)=Average Coumarin emission signal of the 0% Phos. ControlF_(100%)=Average Fluorescein emission signal of the 100% Phos. ControlF_(0%)=Average Fluorescein emission signal of the 0% Phos. ControlGraphing Software

SelectScreen® Kinase Profiling Service uses XLfit from IDBS. The doseresponse curve is curve fit to model number 205 (sigmoidal dose-responsemodel). If the bottom of the curve does not fit between −20% & 20%inhibition, it is set to 0% inhibition. If the top of the curve does notfit between 70% and 130% inhibition, it is set to 100% inhibition.

The activity of MNK proteins can be assayed also by other in vitrokinase assay formats. For example, suitable kinase assays have beendescribed in the literature in Knauf et al., Mol Cell Biol. 2001 August;21(16):5500-11 or in Scheper et al., Mol Cell Biol. 2001 February;21(3):743-54. In general, MNK kinase assays can be performed such that aMNK substrate such as a protein or a peptide, which may or may notinclude modifications as further described below, or others arephosphorylated by MNK proteins having enzymatic activity in vitro. Theactivity of a candidate agent can then be determined via its ability todecrease the enzymatic activity of the MNK protein. The kinase activitymay be detected by change of the chemical, physical or immunologicalproperties of the substrate due to phosphorylation.

In one example, the kinase substrate may have features, designed orendogenous, to facilitate its binding or detection in order to generatea signal that is suitable for the analysis of the substratesphosphorylation status. These features may be, but are not limited to, abiotin molecule or derivative thereof, a glutathione-S-transferasemoiety, a moiety of six or more consecutive histidine residues (SEQ IDNO: 2), an amino acid sequence or hapten to function as an epitope tag,a fluorochrome, an enzyme or enzyme fragment. The kinase substrate maybe linked to these or other features with a molecular spacer arm toavoid steric hindrance.

In another example the kinase substrate may be labelled with afluorophore. The binding of the reagent to the labelled substrate insolution may be followed by the technique of fluorescence polarizationas it is described in the literature. In a variation of this example, afluorescent tracer molecule may compete with the substrate for theanalyte to detect kinase activity by a technique which is know to thoseskilled in the art as indirect fluorescence polarization.

In yet another example, radioactive gamma-ATP is used in the kinasereaction, and the effect of the test agent on the incorporation ofradioactive phosphate in the test substrate is determined relative tocontrol conditions.

It has been shown that the compounds of the invention exhibit low IC50values in in vitro biological screening assays for inhibition of MNK 1and/or MNK 2 kinase activity. The following tables contain the testresults for exemplary compounds.

D. Biological Data

TABLE 1 Biological data of the compounds of the present invention asobtained in assay 1. MNK2 IC50: # IC50 [nM] 1.1 1 1.2 1 1.3 1 1.4 1 1.53 1.6 1 1.7 1 1.8 1 1.9 6 1.10 n.D. 1.11 1 1.12 21 1.13 1 1.14 1 1.15 31.16 1 1.17 2 1.18 2 1.19 106 1.20 1 1.21 2 1.22 25 1.23 4 1.24 1 1.2548 1.26 2 1.27 1 1.28 4 1.29 2 1.30 2 1.31 13 1.32 7 1.33 2 1.34 3 1.355 1.36 2 1.37 4 1.38 12 1.39 7 1.40 3 1.41 3 2.1 1 2.2 4 2.3 5 2.4 4 2.53 2.6 4 2.7 1 2.8 44 2.9 1 2.10 4 2.11 6 2.12 13 2.13 39 2.14 9 2.15 72.16 10 2.17 4 2.18 1 2.19 n.D. 2.20 n.D. 2.21 n.D. 2.22 3 2.23 52 2.244 2.25 2 2.26 n.D. 2.27 46 2.28 4 2.29 3 2.30 7 2.31 2 2.32 n.D. 2.33 32.34 1 2.35 4 2.36 2 2.37 1 2.38 7 2.39 2 2.40 2 2.41 6 2.42 1 2.43 12.44 3 2.45 2 2.46 n.D. 2.47 2 2.48 2 2.49 4 2.50 2 2.51 3 2.52 n.D.2.53 13 2.54 5 2.55 2 2.56 11 2.57 n.D. 2.58 109 2.59 15 2.60 3 2.61 22.62 11 2.63 n.D. 2.64 3 2.65 5 2.66 16 2.67 3 2.68 3 2.69 2 2.70 2 2.713 2.72 30 2.73 4 2.74 3 2.75 3 2.76 5 2.77 164 2.78 3 2.79 1 2.80 192.81 4 2.82 5 2.83 1 2.84 2 2.85 n.D. 2.86 n.D. 2.87 7 2.88 5 2.89 32.90 2 2.91 7 2.92 13 2.93 4 2.94 1 2.95 4 2.96 4 2.97 2 2.98 1 2.99 52.100 6 2.101 5 2.102 5 2.103 7 2.104 4 2.105 2 2.106 1 2.107 10 2.108 32.109 2 2.110 2 2.111 5 2.112 6 2.113 5 2.114 2 2.115 1 2.116 2 2.117 12.118 5 2.119 3 2.120 2 2.121 4 2.122 2 2.123 1 2.124 4 2.125 2 2.126 103.1 111 3.2 4 3.3 5 3.4 n.D. 3.5 5 3.6 69 3.7 36 3.8 22 3.9 10 3.10 83.11 32 3.12 3 3.13 6 3.14 2 4.1 n.D. 4.2 n.D. 4.3 3 4.4 4 4.5 n.D. 4.63 4.7 n.D. 4.8 n.D. 4.9 14 4.10 n.D. 4.11 n.D. 4.12 14 4.13 n.D. 4.14n.D. 4.15 n.D. 5.1 2 5.2 2 5.3 6 5.4 15 5.5 2 5.6 2 5.7 2 6.1 8 6.2 n.D.6.3 2 6.4 2 6.5 n.D. 6.6 2 6.7 2 6.8 n.D. 6.9 5 6.10 8 6.11 31 6.12 126.13 4 6.14 3 6.15 24 6.16 7 6.17 23 6.18 1 6.19 n.D. 6.20 4 7.1 5 7.2 67.3 n.D. 7.4 7 7.5 7 7.6 6 7.7 2 7.8 9 7.9 3 7.10 2 7.11 5 7.12 4 7.13 27.14 7 7.15 10 7.16 1 7.17 1 7.18 2

TABLE 2 Biological data of selected compounds of the present inventionas obtained in assay 2. # IC50 [nM] 1.2 13 1.4 25 1.17 39 1.21 21 1.2418 1.27 11 1.32 149 1.33 110 1.37 28 1.41 74 2.1 11 2.34 17 2.40 56 2.7575 2.76 57 2.95 33 2.102 131 2.103 82 2.107 102 2.115 5 5.5 14 5.6 255.7 43 7.12 87 7.16 25

TABLE 3 % Inhibition of MNK1 at a compound concentration of 1 μM asobtained in assay 2 # % INH 1.1 98 1.4 100 1.9 90 1.10 80 1.12 92 1.1595 1.18 100 1.19 42 1.20 100 1.22 56 1.23 94 1.25 66 1.26 100 1.28 891.29 92 1.30 89 1.31 87 1.35 85 1.36 84 1.38 99 1.40 94 2.2 95 2.3 892.4 97 2.6 92 2.7 98 2.8 64 2.10 92 2.11 92 2.12 24 2.13 73 2.14 52 2.1572 2.16 94 2.17 91 2.19 47 2.21 81 2.23 66 2.24 93 2.27 78 2.28 98 2.3088 2.31 100 2.32 50 2.33 100 2.35 95 2.37 95 2.38 82 2.40 100 2.41 902.44 100 2.45 90 2.46 88 2.47 97 2.49 86 2.51 101 2.52 60 2.53 94 2.5469 2.55 99 2.56 76 2.58 30 2.59 82 2.61 98 2.62 73 2.63 85 2.64 87 2.6598 2.66 88 2.67 85 2.72 71 2.73 97 2.75 100 2.76 100 2.77 55 2.80 732.81 92 2.82 88 2.84 91 2.85 100 2.86 89 2.87 79 2.88 95 2.91 93 2.92 832.94 98 2.97 93 2.98 95 2.99 96 2.100 89 2.101 93 2.104 95 2.106 982.108 99 2.109 100 2.110 100 2.111 89 2.112 89 2.113 90 2.114 96 2.116100 2.117 101 2.118 82 2.120 103 2.121 89 2.122 98 2.123 100 2.124 832.125 94 2.126 93 3.1 50 3.2 101 3.3 95 3.4 92 3.5 101 3.6 80 3.7 81 3.879 3.9 89 3.10 88 3.11 78 3.12 95 3.13 95 4.4 92 4.7 50 4.9 71 4.12 844.13 75 5.1 101 5.3 90 5.4 78 6.1 85 6.5 91 6.6 92 6.7 100 6.9 95 6.1089 6.11 72 6.12 91 6.13 80 6.15 82 6.16 90 6.17 79 6.18 98 6.19 70 6.2093 7.1 86 7.2 82 7.3 72 7.4 88 7.5 77 7.6 99 7.7 97 7.9 96 7.10 100 7.1198 7.13 98 7.14 91 7.15 92 7.17 96 7.18 93Method of Treatment

In view of their ability to inhibit the activity of the MNK1 (MNK1a orMNK1b) and/or MNK2 (MNK2a or MNK2b) kinase, the compounds of generalformula I according to the invention, including the corresponding saltsthereof, are theoretically suitable for the treatment of all thosediseases or conditions which may be affected or which are mediated bythe inhibition of the MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b)kinase.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the inhibition of the MNK1 (MNK1a or MNK1b) and/orMNK2 (MNK2a or MNK2b) kinase in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the inhibition of the MNK1(MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase in a mammal thatincludes the step of administering to a patient, preferably a human, inneed of such treatment a therapeutically effective amount of a compoundor a pharmaceutical composition of the present invention.

Diseases and conditions mediated by inhibitors of the inhibition of theMNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase embracemetabolic diseases or conditions.

The present invention is directed to compounds which are useful in thetreatment and/or prevention of a disease, disorder and/or conditionwherein the inhibition of the activity of the MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a or MNK2b) kinase is of therapeutic benefit, includingbut not limited to the treatment of metabolic diseases, such as obesity,eating disorders, cachexia, diabetes mellitus, metabolic syndrome,hypertension, coronary heart diseases, hypercholesterolemia,dyslipidemia, osteoarthritis, biliary stones and/or sleep apnea anddiseases related to reactive oxygen compounds (ROS defense) such asdiabetes mellitus, neurodegenerative diseases and cancer.

The pharmaceutical compositions of the invention are particularly usefulfor prophylaxis and treatment of obesity, diabetes mellitus and othermetabolic diseases of the carbohydrate and lipid metabolism as statedabove, in particular diabetes mellitus and obesity.

Thus, in a more preferred embodiment of this invention the use of acompound of the invention for the production of a pharmaceuticalcomposition for the prophylaxis or therapy of metabolic diseases isprovided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing a cytokine mediated disorder such as aninflammatory disease is provided.

The pharmaceutical compositions of the invention are thus useful for theprophylaxis or therapy of inflammatory diseases, in particular chronicor acute inflammation, chronic inflammatory arthritis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoidarthritis, gouty arthritis; psoriasis, erythrodermic psoriasis, pustularpsoriasis, inflammatory bowel disease, Crohn's disease and relatedconditions, ulcerative colitis, colitis, diverticulitis, nephritis,urethritis, salpingitis, oophoritis, endomyometritis, spondylitis,systemic lupus erythematosus and related disorders, multiple sclerosis,asthma, meningitis, myelitis, encephalomyelitis, encephalitis,phlebitis, thrombophlebitis, chronic obstructive disease (COPD),inflammatory lung disease, allergic rhinitis, endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjubctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis,oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, dermatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

As already stated above, the compositions of the present invention areparticularly useful for treating or preventing a disease selected fromchronic or acute inflammation, chronic inflammatory arthritis,rheumatoid arthritis, psoriasis, COPD, inflammatory bowel disease,septic shock, Crohn's disease, ulcerative colitis, multiple sclerosisand asthma.

Thus, in a more preferred embodiment of this invention the use of acompound according to the invention for the production of apharmaceutical composition for the prophylaxis or therapy ofinflammatory diseases selected from chronic or acute inflammation,chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma is provided.

In yet a further aspect of the invention the use of a compound of theinvention for the production of a pharmaceutical composition fortreating or preventing cancer, viral diseases or neurodegenerativediseases is provided.

In a further aspect of the invention the use of a compound of thepresent invention for the production of a pharmaceutical composition forinhibiting the activity of the kinase activity of MNK1 (MNK1a or MNK1b)and/or MNK2 (MNK2a, MNK2b) or further variants thereof is provided, inparticular for the prophylaxis or therapy of metabolic diseases,hematopoietic disorders, cancer and their consecutive complications anddisorders. Whereby the prophylaxis and therapy of metabolic diseases ofthe carbohydrate and/or lipid metabolism is preferred.

For the purpose of the present invention, a therapeutically effectivedosage will generally be from about 1 to 2000 mg/day, preferably fromabout 10 to about 1000 mg/day, and most preferably from about 10 toabout 500 mg/day, which may be administered in one or multiple doses.

It will be appreciated, however, that specific dose level of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

It will be appreciated by the person of ordinary skill in the art thatthe compounds of the invention and the additional therapeutic agent maybe formulated in one single dosage form, or may be present in separatedosage forms and may be either administered concomitantly (i.e. at thesame time) or sequentially.

The pharmaceutical compositions of the present invention may be in anyform suitable for the intended method of administration.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to a person skilled in the arton the basis of his specialist knowledge. The preferred ones are thosethat are suitable for the particular formulation and method ofadministration that are desired. The preparations or formulationsaccording to the invention may be prepared using methods known per sethat are familiar to one skilled in the art, such as for example bymixing or combining at least one compound of formula I according to theinvention, or a pharmaceutically acceptable salt of such a compound andone or more excipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Other active substances which are suitable for such combinationsinclude, for example, antidiabetics like insulin, long and short actinginsulin analogues, sulfonylureas, biguanides, DPP-IV inhibitors, SGLT2inhibitors, 11β-HSD inhibitors, glucokinase activators, AMPK activators,Glp-1 receptor agonists, GIP receptor agonists, DGAT inhibitors,PPARgamma agonists, PPARdelta agonists, and other antidiabetics derivedfrom thiazolidinediones, lipid lowering agents such as statines,fibrates, ion exchange resins nicotinic acid derivatives, or HMG-CoAreductase inhibitors, cardiovascular therapeutics such as nitrates,antihypertensiva such as β-blockers, ACE inhibitors, Ca-channelblockers, angiotensin II receptor antagonists, diuretics, thrombocyteaggregation inhibitors, or antineoplastic agents such as alkaloids,alkylating agents, antibiotics, or antimetabolites, or anti-obesityagents. Further preferred compositions are compositions wherein theadditional therapeutic agent is selected from a histamine antagonist, abradikinin antagonist, serotonin antagonist, leukotriene, ananti-asthmatic, an NSAID, an antipyretic, a corticosteroid, anantibiotic, an analgetic, a uricosuric agent, chemotherapeutic agent, ananti gout agent, a bronchodilator, a cyclooxygenase-2 inhibitor, asteroid, a 5-lipoxygenase inhibitor, an immunosuppressive agent, aleukotriene antagonist, a cytostatic agent, an antineoplastic agent, amTor inhibitor, a Tyrosine kinase inhibitor, antibodies or fragmentsthereof against cytokines and soluble parts (fragments) of cytokinereceptors.

More particularly preferred are compounds such as human NPH insulin,human lente or ultralente insulin, insulin Lispro, insulin Aspart,insulin Glulisine, insulin detemir or insulin Glargine, metformin,phenformin, acarbose, miglitol, voglibose, pioglitazone, rosiglizatone,rivoglitazone, aleglitazar, alogliptin, saxagliptin, sitagliptin,vildagliptin, exenatide, liraglutide, albiglutide, pramlintide,carbutamide, chlorpropamide, glibenclamide (glyburide), gliclazide,glimepiride, glipizide, gliquidone, tolazamide, tolbutamide, atenolol,bisoprolol, metoprolol, esmolol, celiprolol, talinolol, oxprenolol,pindolol, propanolol, bupropanolol, penbutolol, mepindolol, sotalol,certeolol, nadolol, carvedilol, nifedipin, nitrendipin, amlodipin,nicardipin, nisoldipin, diltiazem, enalapril, verapamil, gallopamil,quinapril, captopril, lisinopril, benazepril, ramipril, peridopril,fosinopril, trandolapril, irbesatan, losartan, valsartan, telmisartan,eprosartan, olmesartan, hydrochlorothiazide, piretanid, chlorotalidone,mefruside, furosemide, bendroflumethiazid, triamterene, dehydralazine,acetylsalicylic acid, tirofiban-HCl, dipyramidol, triclopidin,iloprost-trometanol, eptifibatide, clopidogrel, piratecam, abciximab,trapidil, simvastatine, bezafibrate, fenofibrate, gemfibrozil,etofyllin, clofibrate, etofibrate, fluvastatine, lovastatine,pravastatin, colestyramide, colestipol-HCl, xantinol nicotinat, inositolnicotinat, acipimox, nebivolol, glyceroInitrate, isosorbide mononitrate,isosorbide dinitrate, pentaerythrityl tetranitrate, indapamide,cilazepril, urapidil, eprosartan, nilvadipin, metoprolol, doxazosin,molsidormin, moxaverin, acebutolol, prazosine, trapidil, clonidine,vinca alkaloids and analogues such as vinblastin, vincristin, vindesin,vinorelbin, podophyllotoxine derivatives, etoposid, teniposid,alkylating agents, nitroso ureas, N-lost analogues, cycloplonphamid,estamustin, melphalan, ifosfamid, mitoxantron, idarubicin, doxorubicin,bleomycin, mitomycin, dactinomycin, daptomycin, docetaxel, paclitaxel,carboplatin, cisplatin, oxaliplatin, BBR3464, satraplatin, busulfan,treosulfan, procarbazine, dacarbazine, temozolomide, chlorambucil,chlormethine, cyclophosphamide, ifosfamide, melphalan, bendamustine,uramustine, ThioTEPA, camptothecin, topotecan, irinotecan, rubitecan,etoposide, teniposide, cetuximab, panitumumab, trastuzumab, rituximab,tositumomab, alemtuzumab, bevacizumab, gemtuzumab, aminolevulinic acid,methyl aminolevulinate, porfimer sodium, verteporfin, axitinib,bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib,lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib,vandetanib, retinoids (alitretinoin, tretinoin), altretamine, amsacrine,anagrelide, arsenic trioxide, asparaginase (pegaspargase), bexarotene,bortezomib, denileukin diftitox, estramustine, ixabepilone, masoprocol,mitotane, testolactone, tipifarnib, abetimus, deforolimus, everolimus,gusperimus, pimecrolimus, sirolimus, tacrolimus, temsirolimus,antimetabolites such as cytarabin, fluorouracil, fluoroarabin,gemcitabin, tioguanin, capecitabin, combinations such asadriamycin/daunorubicin, cytosine arabinosid/cytarabine, 4-HC, or otherphosphamides.

Other particularly preferred compounds are compounds such as clemastine,diphenhydramine, dimenhydrinate, promethazine, cetirizine, astemizole,levocabastine, loratidine, terfenadine, acetylsalicylic acid, sodoumsalicylate, salsalate, diflunisal, salicylsalicylic acid, mesalazine,sulfasalazine, osalazine, acetaminophen, indomethacin, sulindac,etodolac, tolmetin, ketorolac, bethamethason, budesonide, chromoglycinicacid, dimeticone, simeticone, domperidone, metoclopramid, acemetacine,oxaceprol, ibuprofen, naproxen, ketoprofen, flubriprofen, fenoprofen,oxaprozin, mefenamic acid, meclofenamic acid, pheylbutazone,oxyphenbutazone, azapropazone, nimesulide, metamizole, leflunamide,eforicoxib, lonazolac, misoprostol, paracetamol, aceclofenac,valdecoxib, parecoxib, celecoxib, propyphenazon, codein, oxapozin,dapson, prednisone, prednisolon, triamcinolone, dexibuprofen,dexamethasone, flunisolide, albuterol, salmeterol, terbutalin,theophylline, caffeine, naproxen, glucosamine sulfate, etanercept,ketoprofen, adalimumab, hyaluronic acid, indometacine, proglumetacinedimaleate, hydroxychloroquine, chloroquine, infliximab, etofenamate,auranofin, gold, [²²⁴Ra]radium chloride, tiaprofenic acid,dexketoprofen(trometamol), cloprednol, sodium aurothiomalateaurothioglucose, colchicine, allopurinol, probenecid, sulfinpyrazone,benzbromarone, carbamazepine, lornoxicam, fluorcortolon, diclofenac,efalizumab, idarubicin, doxorubicin, bleomycin, mitomycin, dactinomycin,daptomycin, cytarabin, fluorouracil, fluoroarabin, gemcitabin,tioguanin, capecitabin, adriamydin/daunorubicin, cytosinearabinosid/cytarabine, 4-HC, or other phosphamides, penicillamine, ahyaluronic acid preparation, arteparon, glucosamine, MTX, solublefragments of the TNF-receptor (such as etanercept (Enbrel)) andantibodies against TNF (such as infliximab (Remicade), natalizumab(Tysabri) and adalimumab (Humira)).

EXAMPLES Preliminary Remarks

The hereinafter described compounds have been characterized throughtheir characteristic mass after ionisation in a mass-spectrometer, theirRf-value on thin-layer-chromatography plate and/or their retention timeon an analytical HPLC.

List of Abbreviations

-   ACN Acetonitrile-   AcOH acetic acid-   aq. Aqueous-   BOC tert-butoxy-carbonyl--   ° C. degree celsius-   dba Dibenzylideneacetone-   DCM Dichloromethane-   DMAP 4-Dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   ESI-MS electrospray ionisation mass spectrometry-   EtOAc ethyl acetate-   EtOH Ethanol-   FC Flash-cromatography, SiO₂ is used if no further details given-   h Hour-   HPLC high performance liquid chromatography-   L Liter-   MeOH Methanol-   min Minute-   ml Milliliter-   MS mass spectrum-   μW Reaction was performed in a microwave-   n.d. not determined-   NH4OH solution of NH₃ in water-   NMP N-Methyl-2-pyrrolidinon-   psi pound per square inch-   RT room temperature (about 20° C.)-   R_(t) retention time-   TF/TFA trifluoroacetic acid-   THF Tetrahydrofuran-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene-   XtalFluor-E (Diethylamino)difluorosulfonium tetrafluoroborate    HPLC Methods

HPLC-A: Agilent 1200 with DA- and MS-detector, XBridge C18_3.0 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100.0 3.0

HPLC-B: Agilent 1200 with DA- and MS-Detector, Sunfire C18_3.0 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100.0 3.0

HPLC-C: Waters Acquity with DA- and MS-detector and CTC Autosampler, BEHC18_2.1 × 30 mm, 1.7 μm (Waters), 60° C. % Sol % Sol Time [min] [H₂O0.1% NH₄OH] [Acetonitrile] Flow [ml/min] 0.0 98.0 2.0 1.5 1.2 0.0 100.01.5 1.4 0.0 100.0 1.5 1.45 98.0 2.0 1.5

HPLC-D: Waters 1525 with DA- and MS-detector, Sunfire C18_4.6 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0100.0 3.0 2.2 0.0 100.0 4.5 2.4 0.0 100.0 4.5

HPLC-E: Agilent 1200 with DA- and MS-detector, StableBond C18_3.0 × 30mm, 1.8 μm (Agilent), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100.0 3.0

HPLC-F: Waters 1525 with DA- and MS-detector, XBridge C18_4.6 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 4.0 0.15 97.0 3.0 3.0 2.15 0.0100.0 3.0 2.2 0.0 100.0 4.5 2.4 0.0 100.0 4.5

HPLC-G: Waters 1525 with DA- and MS-detector, Sunfire C18_4.6 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol [Methanol]Flow [ml/min] 0.0 95.0 5.0 4.0 0.05 95.0 5.0 3.0 2.05 0.0 100.0 3.0 2.10.0 100.0 4.5 2.4 0.0 100.0 4.5

HPLC-H: Agilent 1200 with DA- and MS-detector, XBridge C18_3 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol [Methanol]Flow [ml/min] 0.0 95.0 5.0 2.2 0.3 95.0 5.0 2.2 1.5 0.0 100.0 2.2 1.550.0 100.0 2.9 1.65 0.0 100.0 2.9

HPLC-I: Agilent 1100 with DAD, Waters autosampler and MS-detector,SunFire C18_4.6 × 30 mm, 3.5 μm (Waters), 60° C. % Sol Time [min] [H₂O0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 98.0 2.0 2.5 1.5 0.0100.0 2.5 1.8 0.0 100.0 2.5

HPLC-J: Agilent 1100 with DAD, Gilson autosampler and MS-detector,SunFire C18_4.6 × 30 mm, 3.5 μm (Waters), 60° C. % Sol Time [min] [H₂O0.1% TFA] % Sol [Acetonitril] Flow [ml/min] 0.0 98.0 2.0 2.5 1.5 0.0100.0 2.5 1.8 0.0 100.0 2.5

HPLC-K: Waters Acquity with 3100 MS, XBridge BEH C18_3.0 × 30 mm, 1.7 μm(Waters), 60° C. % Sol % Sol Time [min] [H₂O 0.1% NH₄OH] [Acetonitrile]Flow [ml/min] 0.0 95.0 5.0 1.5 0.7 0.1 99.9 1.5 0.8 0.1 99.9 1.5 0.8195.0 5.0 1.5 1.1 95.0 5.0 1.5

HPLC-L: Waters Acquity with DA- and MS-detector, BEH C18_2.1 × 30 mm,1.7 μm (Waters), 60° C. % Sol % Sol Time [min] [H₂O 0.1% NH₄OH][Acetonitrile] Flow [ml/min] 0.0 95.0 5.0 1.5 0.8 0.1 99.9 1.5 0.9 0.199.9 1.5

HPLC-M: Agilent 1200 with DA- and MS-detector, XBridge C18_3.0 × 30 mm,2.5 μm (Waters), 60° C. % Sol % Sol Time [min] [H₂O 0.1% NH₄OH][Acetonitrile] Flow [ml/min] 0.0 97.0 3.0 2.2 0.2 97.0 3.0 2.2 1.2 0.0100.0 2.2 1.25 0.0 100.0 3.0 1.4 0.0 100.0 3.0

HPLC-N: Waters Acquity with DA- and MS-detector and CTC autosampler,XBridge C18_3.0 × 30 mm, 2.5 μm (Waters), 60° C. % Sol % Sol Time [min][H₂O 0.1% NH₄OH] [Acetonitrile] Flow [ml/min] 0.0 98.0 2.0 2.0 1.2 0.0100.0 2.0 1.4 0.0 100.0 2.0

HPLC-O: Agilent 1200 with DA- and MS-detector, Halo C18_2.1 × 30 mm, 2.7μm (Advanced Materials Technology), 60° C. % Sol Time [min] [H₂O 0.1%TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 93.0 7.0 3.0 0.1 93.0 7.03.0 0.11 60.0 40.0 3.0 0.5 0.0 100.0 3.0

HPLC-P: Agilent 1100 with DAD, CTC autosampler and Waters MS-detector,XBridge C18_4.6 × 30 mm, 3.5 μm (Waters), 60° C. % Sol % Sol Time [min][H₂O 0.1% NH₄OH] [Acetonitrile] Flow [ml/min] 0.0 98.0 2.0 2.5 1.5 0.0100.0 2.5 1.8 0.0 100.0 2.5

HPLC-Q: Waters Acquity with 3100 MS, Sunfire C18_2.1 × 50 mm, 2.5 μm(Waters), 60° C. % Sol % Sol [Acetonitrile Time [min] [H₂O 0.1% TFA]0.08% TFA] Flow [ml/min] 0.0 95.0 5.0 1.5 0.75 0.0 100.0 1.5 0.85 0.0100.0 1.5

HPLC-R: Agilent 1100 with DAD, Waters autosampler and MS-detector,SunFire C18_4.6 × 30 mm, 3.5 μm (Waters), 50° C. % Sol Time [min] [H₂O0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 95.0 5.0 4.0 1.2 0.0100.0 4.0 1.8 0.0 100.0 4.0

HPLC-S: Waters 1525 with DA- and MS-detector, XBridge C18_4.6 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H ₂O 0.1% TFA] % Sol[Methanol] Flow [ml/min] 0.0 95.0 5.0 4.0 0.05 95.0 5.0 3.0 2.05 0.0100.0 3.0 2.1 0.0 100.0 4.5 2.4 0.0 100.0 4.5

HPLC-T: Agilent 1100 with DA- and MS-detector, StableBond C18_4.6 × 30mm, 3.5 μm (Agilent), 60° C. % Sol Time [min] [H₂O 0.1% TFA] % Sol[Methanol] Flow [ml/min] 0.0 95.0 5.0 4.0 0.15 95.0 5.0 4.0 1.7 0.0100.0 4.0 2.25 0.0 100.0 4.0

HPLC-U: Agilent 1200 with DA- and MS-detector, XBridge C18_3.0 × 30 mm,2.5 μm (Waters), 60° C. % Sol Time [min] [H₂O 0.1% NH₄OH] % Sol[Methanol] Flow [ml/min] 0.0 95.0 5.0 2.2 0.3 95.0 5.0 2.2 1.5 0.0 100.02.2 1.55 0.0 100.0 2.9 1.7 0.0 100.0 2.9

HPLC-V: Agilent 1100 with DA-detector, XBridge C18_3.0 × 30 mm, 2.5 μm(Waters), 60° C. % Sol % Sol Time [min] [H₂O 0.1% NH₄OH] [Acetonitrile]Flow [ml/min] 0.0 98.0 2.0 2.0 1.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0

HPLC-W: XBridge BEH C18_2.1 × 30 mm, 1.7 μm (Waters), 60° C. % Sol Time[min] [H₂O, 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 99 1 1.60.02 99 1 1.6 1.00 0 100 1.6 1.10 0 100 1.6

HPLC-X: Sunfire C18_3.0 × 30 mm, 2.5 μm (Waters), 60° C. % Sol Time[min] [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 98.0 2.0 2.01.2 0.0 100.0 2.0 1.4 0.0 100.0 2.0

HPLC-Y: XBridge C18, 4.6 × 30 mm, 2.5 μm (Waters), 60° C. % Sol Time[min] [H₂O, 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 60 40 40.15 60 40 3 2.15 0 100 3 2.20 0 100 4.5 2.40 0 100 4.5

HPLC-Z: Sunfire C18_3.0 × 30 mm, 2.5 μm (Waters), 60° C. % Sol Time[min] [H₂O 0.1% TFA] % Sol [Acetonitrile] Flow [ml/min] 0.0 99.0 1.0 2.00.9 0.0 100.0 2.0 1.1 0.0 100.0 2.0

Preparation of Intermediates Intermediate I.1:2-amino-4-bromo-6-fluoro-benzonitrile

5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile in 200 ml of asolution of NH₃ in ethanol and heated in a pressure vessel to 90° C. for20 h. After cooling to RT the solvent is evaporated and the residuetaken up in water/DCM. The organic phase is separated, dried andevaporated.

Yield: 4.9 g (99%), ESI-MS: m/z=213/215 (M−H)⁻, R_(t)(HPLC): 1.72 min(HPLC-S)

Intermediate II.1:N′-(5-bromo-2-cyano-3-fluoro-phenyl)-N,N-dimethyl-formamidine

17.0 g (79.1 mmol) 2-amino-4-bromo-6-fluoro-benzonitrile in 140 ml ofN,N-dimethylformamide dimethyl acetal are heated to 120° C. for 2 h.After cooling RT the solvent is evaporated and the residue taken up indiethyl ether, filtered and dried.

Yield: 20.5 g (96%), ESI-MS: m/z=270/272 (M+H)⁺, R_(t)(HPLC): 0.83 min(HPLC-H)

The following intermediates are prepared in a similar manner tointermediate II.1 from the corresponding anilines which are commerciallyavailable or can be obtained according to (a) U.S. Pat. No. 3,987,192and (b) J. Med. Chem. 1981, 24 (6), 742.

ESI-MS m/z Name Structure Starting Material M + H⁺ R_(t)(HPLC) II.2

2-amino-4-bromo-6- methyl-benzonitrile^((a)) 266/268 0.57 min (HPLC-A)II.3

2-amino-6-chloro- benzonitrile^((b)) 208 0.47 min (HPLC-A) II.4

2-amino-6-bromo- benzonitrile^((b)) 252/254 0.53 min (HPLC-A)

Intermediate II.5:N′-[3-chloro-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

0.2 g (0.96 mmol) intermediate II.3, 0.2 g (0.67 mmol)bis(pinacolato)diborane, 26 mg (0.01 mmol)4,4′-di-tert-butyl-[2,2′]bipyridinyl and 40 mg (0.06 mmol)chloro(1,5-cyclooctadiene)iridium(I) dimer are heated in heptane atreflux for 2 days. After cooling to RT the solvent is evaporated and theresidue taken up in water/EtOAc. The organic phase is separated, driedand evaporated yielding the crude corresponding boronic acid derivativewhich is dissolved in MeOH. 0.1 g (0.75 mmol) dimethylsulfoximine (V.1)and 14 mg (0.08 mmol) copper(II) acetate are added and the reactionmixture stirred at RT over night. After addition of MeOH andconcentrated aqueous NH₃ solution, the solvent is evaporated and theresidue purified by FC.

Yield: 0.1 g (58%), ESI-MS: m/z=299 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-M)

Intermediate II.6:N′-[3-bromo-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

Prepared in a similar manner as intermediate II.5 from intermediatesII.4 and V.1.

ESI-MS: m/z=343/345 (M+H)⁺, R_(t)(HPLC): 0.66 min (HPLC-E)

Intermediate II.7N′-[3-chloro-2-cyano-5-[(1-oxothiolan-1-ylidene)amino]phenyl]-N,N-dimethyl-formamidine

Prepared in a similar manner as intermediate II.5 from intermediatesII.3 and V.5.

ESI-MS: m/z=325/327 (M+H)⁺, R_(t)(HPLC): 0.75 min (HPLC-M)

Intermediate II.8:N′-(5-bromo-2-cyano-3-methoxy-phenyl)-N,N-dimethyl-formamidine

3.0 g (11.1 mmol) intermediate II.1, 17.4 g MeOH (555.4 mmol), 4.3 g(13.3 mmol) Cs₂CO₃ in 50 ml dioxane are heated in a pressure vessel for5 h to reflux. After cooling to RT the solvent is evaporated and theresidue purified by FC.

Yield: 2.4 g (75%), ESI-MS: m/z=282/284 (M+H)⁺, R_(t)(HPLC): 0.97 min(HPLC-D)

Intermediate II.9:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-methyl-phenyl]-N,N-dimethyl-formamidine

To 0.5 g (1.9 mmol) intermediate II.2 in 20 ml dioxane 0.2 g (2.3 mmol)dimethylsulphoximine (V.1), 0.1 g (0.4 mmol) 2-(di-t-butylphosphino)biphenyl, 0.1 g (0.14 mmol) Pd₂dba₃ and 0.3 g (2.7 mmol) sodiumtert-butoxide are added and the mixture is heated to 80° C. for 1 h. Thereaction mixture is diluted with water, acidified with citric acid andextracted with EtOAc, then basified and extracted with DCM. The organicphases are pooled dried and evaporated.

Yield: 0.4 g (83%), ESI-MS: m/z=279 (M+H)⁺, R_(t)(HPLC): 0.59 min(HPLC-H)

Intermediate II.10:N′-[2-cyano-3-cyclopropyl-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To 100 mg (0.29 mmol) intermediate II.6 in 20 ml dioxane 25 mg (0.29mmol) cyclopropylboronic acid, 0.1 g (0.4 mmol)1,1′-bis(diphenylphosphino)ferrocenedichloro-palladium(II), 121 mg (2.7mmol) potassium carbonate are added and the reaction mixture is heatedto 80° C. over night. The reaction mixture is cooled to RT, diluted withMeOH and evaporated. The residue is purified by HPLC.

Yield: 70 mg (79%), ESI-MS: m/z=305 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-E)

Intermediate II.11:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-(trifluoromethyl)phenyl]-N,N-dimethyl-formamidine

prepared in a similar manner as intermediate II.5 from2-amino-6-(trifluoromethyl)benzonitrile and intermediate V.1.

ESI-MS: m/z=242 (M+H)⁺, R_(t)(HPLC): 0.71 min (HPLC-E)

Intermediate II.12:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-(difluoromethyl)phenyl]-N,N-dimethyl-formamidine

prepared in a similar manner as intermediate II.5 from2-amino-6-(difluoromethyl)benzonitrile and intermediate V.1.

ESI-MS: m/z=315 (M+H)⁺, R_(t)(HPLC): 0.64 min (HPLC-E)

Intermediate II.13:N′-[3-(azetidin-1-yl)-2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To 100 mg (0.29 mmol) intermediate II.6 in 2 ml dioxane 33 mg (0.58mmol) azetidine, 34 mg (0.06 mmol) Xanthphos, 27 mg (0.03 mmol) Pd₂dba₃,124 mg (0.44 mmol) Cs₂CO₃ are added and the reaction mixture is heatedto reflux for 6 h. The reaction mixture is cooled to RT and evaporated.The residue is purified by HPLC.

Yield: 90 mg (71%), ESI-MS: m/z=320 (M+H)⁺, R_(t)(HPLC): 0.66 min(HPLC-E)

Intermediate II.14:N′-[2-cyano-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-3-hydroxy-phenyl]-N,N-dimethyl-formamidine

Step 1: 5.0 g (18.5 mmol) intermediate II.1, 3.4 g(2,4-dimethoxyphenyl)methanol (20.4 mmol), 7.2 g (22.2 mmol) Cs₂CO₃ in80 ml dioxane are heated to reflux for 2 days. After cooling to RTreaction mixture is diluted with water and the precipitate is filteredoff.

Yield: 7.0 g (90%), ESI-MS: m/z=418/420 (M+H)⁺, R_(t)(HPLC): 0.93 min(HPLC-E)

Step 2: To 7.0 g (16.8 mmol) intermediate II.14 Step 1 in dioxane 1.6 g(16.8 mmol) dimethylsulphoximine (V.1), 1.0 g (3.3 mmol)2-(di-t-butylphosphino) biphenyl, 1.2 g (1.3 mmol) Pd₂dba₃ and 2.3 g(24.1 mmol) sodium tert-butoxide are added and the mixture is heated to80° C. for 2 h. The reaction mixture is diluted with water extractedwith DCM. The organic phases are pooled dried and evaporated.

Yield: 7.0 g (97%), ESI-MS: m/z=431 (M+H)⁺, R_(t)(HPLC): 0.82 min(HPLC-E)

Step 3: To 1.5 g (3.5 mmol) intermediate II.14 Step 2 in DCM 1.5 ml TFAare added and the mixture is stirred at RT for 1 h. The reaction mixtureis evaporated and the residual is triturated with DCM and MeOH, filteredand dried.

Yield: 0.97 g (71%), ESI-MS: m/z=281 (M+H)⁺, R_(t)(HPLC): 0.25 min(HPLC-E)

Intermediate II.15:N′-[2-cyano-3-(difluoromethoxy)-5-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To 500 mg (1.3 mmol) intermediate II.14 in mixture of acetonitrile/water1:1, 1.4 g (25.4 mmol) KOH are added and the reaction mixture is cooledto −78° C. 0.5 ml (Bromo-difluoro-methyl)-phosphonic acid diethyl ester(2.5 mmol) are added to the frozen mixture. The reaction mixture isslowly warmed to RT and stirred for 2 h. The reaction mixture is dilutedwith water, the precipitate is filtered off and the filtrate isextracted with DCM. The organic phases are pooled dried and evaporated.

Yield: 54 mg (13%), ESI-MS: m/z=331 (M+H)⁺, R_(t)(HPLC): 0.67 min(HPLC-E)

Intermediate II.16:N′-[2-cyano-3-(cyclopropoxy)-5-[[dimethyl(oxo-λ⁶-sulfanylidene]amino]phenyl]-N,N-dimethyl-formamidine

To a mixture of 100 mg (0.25 mmol) intermediate II.14* TFA, 0.3 g (2.5mmol) cyclopropyl bromide, 0.3 g (1.01 mmol) Cs₂CO₃, 13 mg KI (0.08mmol), 16 mg (0.13 mmol) diisopropyl-ethyl-amine and dimethylacetamideis warmed to 150° C. and stirred over night. The reaction mixture isdiluted with water and extracted with DCM. The organic phases are pooleddried and evaporated.

Yield: 82 mg (100%), ESI-MS: m/z=321 (M+H)⁺, R_(t)(HPLC): 0.69 min(HPLC-E)

Intermediate II.17:N′-[3-chloro-2-cyano-5-[(1-oxothietan-1-ylidene)amino]phenyl]-N,N-dimethyl-formamidine

Prepared in a similar manner as intermediate II.5 from intermediatesII.3 and V.3.

ESI-MS: m/z=311/313 (M+H)⁺, R_(t)(HPLC): 0.73 min (HPLC-M)

Intermediate III.1:(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

2.2 ml (20.0 mmol) 2,4-difluoro-1-nitro-benzene and 2.9 g (20.0 mmol)1,4:3,6-dianhydro-D-mannitol in 70 ml THF are cooled to −5° C. 20 ml(20.0 mml) 1M LiHMDS in THF are added dropwise and the reaction mixtureis allowed to warm to RT and stirred over night. 1M HCl is added and themixture is extracted with EtOAc. The organic phases are pooled andwashed with water, dried and evaporated. The residue is purified by FC.

Yield: 2.7 g (47%), ESI-MS: m/z=286 (M+H)⁺, R_(t)(HPLC): 0.80 min(HPLC-H)

Intermediate III.2:(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

To 0.9 g (3.0 mmol)(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(III.1), 0.1 g (0.3 mmol) tetrabutylammonium iodide and 1.3 ml (7.8mmol) of a 6 mol/l aqueous NaOH solution in 15 ml DCM 0.3 ml (3.6 mmol)dimethyl sulfate are added dropwise and the mixture is stirred at RT for24 h. Additional 1.3 ml (7.8 mmol) of a aqueous 6 mol/l NaOH solutionand 0.3 ml (3.6 mml) dimethyl sulfate are added and the mixture isstirred at RT over night. The reaction mixture is washed with water,dried and evaporated. The residue is purified by FC.

Yield: 0.8 g (85%), ESI-MS: m/z=300 (M+H)⁺, R_(t)(HPLC): 0.90 min(HPLC-H)

Intermediate III.3:[(3R,3aR,6S,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate

2.9 g (5.0 mmol)(3S,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(prepared as described for III.1 from 2,4-difluoro-1-nitro-benzene and1,4:3,6-dianhydro-D-sorbitol) and 1.2 g (15.0 mmol) pyridine in DCM arecooled to 0° C. 2.0 ml (12.0 mml) trifluoromethanesulfonic anhydride isadded dropwise and after 1 h the reaction mixture is allowed to warm toRT and stirred over night. The reaction mixture is washed with water,10% citric acid, water, dried and evaporated.

Yield: 4.0 g (96%), ESI-MS: m/z=418 (M+H)⁺, R_(t)(HPLC): 0.95 min(HPLC-A)

Intermediate III.4:(3aR,6R,6aS)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

To 4.0 g (9.6 mmol)[(3R,3aR,6S,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate(intermediate III.3) in acetonitrile 1.1 g (28.8 mmol) sodiumborohydride are added. The reaction mixture is stirred at RT for 10days. The reaction mixture is evaporated, taken up in ice water,carefully acidified with aqueous 4 mol/l HCl and extracted with EtOAc.The organic phases are pooled, washed with water, dried and evaporated.The residue is purified by FC.

Yield: 1.6 g (62%), ESI-MS: m/z=270 (M+H)⁺, R_(t)(HPLC): 0.75 min(HPLC-A)

Intermediate III.5:(3S,3aR,6R,6aS)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-carbonitrile

0.4 g (1.0 mmol)[(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate(prepared as described for III.3 from III.1), 0.1 g (1.5 mmol) potassiumcyanide and 0.3 g (1.0 mmol) 18-crown-6 in THF is stirred at RT for 3 h.The reaction mixture is filtered through celite and evaporated. Theresidue is taken up in EtOAc washed with water, dried and evaporated.The residue is purified by FC.

Yield: 0.2 g (78%), ESI-MS: m/z=295 (M+H)⁺, R_(t)(HPLC): 0.76 min(HPLC-A)

Intermediate III.6:(3R,3aR,6S,6aR)-3-benzyloxy-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

To 6.0 g (25.2 mmol)(3R,3aR,6R,6aR)-6-benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol,3.3 g (21 mmol) 5-fluoro-2-nitro-phenol and 8.3 g (31.5 mmol) triphenylphosphine in 150 ml THF 7.3 g (31.5 mml) di-tert-butyl azodicarboxylatein 30 ml THF are added dropwise and the reaction mixture is stirred at40° C. for 2 h. The reaction mixture is evaporated and the residue ispurified by FC.

Yield: 6.0 g (76%), ESI-MS: m/z=376 (M+H)⁺, R_(t)(HPLC): 0.95 min(HPLC-A)

Intermediate III.7:(3R,3aR,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one

To 1.4 g (5.0 mmol)(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(III.1), 2.5 g molecular sieves 4 Å in DCM 1.2 g (10.0 mmol)N-methyl-morpholin-N-oxide and after 5 min 0.1 g (0.25 mmol)tetrapropylammonium perruthenate are added. The reaction mixture isstirred at RT for 30 min and purified by FC.

Yield: 0.9 g (64%), ESI-MS: m/z=282 (M−H)⁻, R_(t)(HPLC): 0.55 min(HPLC-M)

Intermediate III.8:(3R,3aR,6R,6aR)-3-(5-fluoro-2-nitro-phenoxy)-6-isopropoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

To 0.9 g (3.2 mmol)(3R,3aR,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one(III.7) and 0.1 g (0.32 mmol) FeCl₃ in acetonitrile 1.3 g (9.7 mmol)isopropoxytrimethylsilane and 1.3 g (9.7 mmol) triethylsilane are addedand the reaction mixture is stirred at RT for 5 h. Additional FeCl₃ isadded and the reaction mixture are stirred over night. The reactionmixture is quenched by addition of pH 7 buffer solution and extractedwith EtOAc. The organic phases are pooled, dried and evaporated. Theresidue is purified by FC.

Yield: 0.6 g (62%), ESI-MS: m/z=328 (M+H)⁺, R_(t)(HPLC): 0.82 min(HPLC-M)

Intermediate III.9:(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-6-methyl-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-ol

1.6 g (5.7 mmol)(3R,3aR,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one(III.7) in THF are cooled to −70° C. 3.5 ml (5.7 mmol) 1.6 mol/l methyllithium in diethyl ether are added dropwise and the reaction mixture isallowed to reach RT and stirred for 2.5 h. Aqueous NH₄Cl solution anddiethyl ether are added and the organic layer is separated, dried andevaporated. The residue is purified by FC (Al₂O₃).

Yield: 0.5 g (32%), ESI-MS: m/z=300 (M+H)⁺, R_(t)(HPLC): 0.68 min(HPLC-M)

Intermediate III.10:(3R,3aR,6R,6aR)-3-ethoxy-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

To 1.1 g (3.8 mmol)(3R,3aR,6R,6aR)-6-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol(III.1), 0.88 g (5.6 mmol) ethyl iodide in DMF, 0.2 g (4.1 mmol) NaH(55% in mineral oil) are added and the temperature is kept below 35° C.The mixture is stirred at RT for 1 h. Water and EtOAc are added and theorganic layer is separated, washed with water, dried and evaporated. Theresidue was purified by FC.

Yield: 0.5 g (40%), ESI-MS: m/z=314 (M+H)⁺, R_(t)(HPLC): 0.77 min(HPLC-M)

Intermediate III.11:(3R,3aR,6S,6aS)-6-fluoro-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan

3.7 g (8.9 mmol)[(3R,3aR,6R,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate(prepared as described for III.3 from III.1) in 53.2 ml of a 1M solutionof tetrabutylammonium flouride in THF (53.2 mmol) is stirred at RT for 3h. Water and DCM are added and the organic layer is separated, washedwith water, dried and evaporated. The residue was purified by FC.

Yield: 2.3 g (89%), ESI-MS: m/z=288 (M+H)⁺, R_(t)(HPLC): 0.80 min(HPLC-A)

Intermediate IV.1:(3R,3aR,6R,6aR)-6-(2-amino-5-fluoro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

0.3 g 10% Pd/C are added to 2.6 g (9.1 mmol) III.1 in 70 ml EtOAc. Thereaction mixture is stirred at RT for 5 h under a hydrogen atmosphere(50 psi). The catalyst is filtered off and the filtrate is evaporated.

Yield: 2.3 g (99%), ESI-MS: m/z=256 (M+H)⁺, R_(t)(HPLC): 0.34 min(HPLC-H)

The following Intermediates are prepared in two steps in a similarmanner to intermediate IV.1 from the corresponding starting materials:

Structure Starting Material IV.A

IV.B

IV.C

IV.D

IV.E

IV.F

— IV.G

and alcohols which are commercially available or can be obtainedaccording to (a) Liebigs Ann. 1970, Vol. 736, 75, (b) J. Am. Chem. Soc.1998, Vol. 120(23), 5713, (c) J. Med. Chem. 2005, Vol. 48(6), 1813, (d)J. Med. Chem. 1996, Vol. 39(17), 3278.

ESI-MS m/z Name Structure R Alcohol M + H⁺ R_(t)(HPLC) IV.2 IV.A

1,4-dioxepan-6-ol^((a)) 434 1.15 min (HPLC-E) IV.3 IV.A

4-Methoxy cyclohexanol* 223 IV.4 IV.A

(4-Hydroxy- cyclohexyl)-carbamic acid tert-butyl ester 308 IV.5 IV.A

tert-butyl (3R)-3- hydroxypiperidine-1- carboxylate 294 1.17 min(HPLC-U) IV.6 IV.A

1,4:3,6-Dianhydro-D- mannitol 239 0.28 min (HPLC-H) IV.7 IV.B

cyclopentanol 196 IV.8 IV.B

tert-butyl (3R)-3- hydroxypyrrolidine-1- carboxylate 297 IV.9 IV.B

1,4-dioxepan-6-ol^((a)) 228 0.73 min (HPLC-T) IV.10 IV.B

1- methylcyclohexane- 1,4-diol^((b)*) 240 IV.11 IV.B

rac-(3aR,4S,6aS)- 2,3,3a,4,5,6a- hexahydrofuro[2,3- b]furan-4-ol^((c))240 0.61 min (HPLC-H) IV.12 IV.B

1,4:3,6-Dianhydro-D- sorbitol 256 0.31 min (HPLC-H) IV.13 IV.B

1,4:3,6-Dianhydro-D- iditol 256 0.79 min (HPLC-U) IV.14 IV.C

tetrahydropyran-4-ol 272 IV.15 IV.D

cyclopentanol IV.16 IV.D

tetrahydropyran-4-ol 237 IV.17 IV.E

trans-cyclohexane- 1,4-diol 233 0.76 min (HPLC-E) IV.18 IV.G

1,4:3,6-Dianhydro-D- mannitol 272/274 0.51 min (HPLC-B) IV.19 IV.B

1,3-dioxan-5-ol 214 IV.20 IV.B

1- methylcyclopropanol 182 0.72 min (HPLC-E) IV.21 IV.B

1- methylcyclobutanol 196 0.79 min (HPLC-E) IV.22 IV.B

1-(trifluoromethyl)- cyclobutanol 250 0.95 min (HPLC-E) IV.23 IV.B

3-methyloxetan-3-ol 198 0.59 min (HPLC-E) IV.24 IV.B

3-methyltetra- hydrofuran-3-ol 212 0.66 min (HPLC-E) IV.25 IV.B

2,3,3a,4,6,6a- hexahydrofuro[3,4- b]furan-3-ol^((d)) 240 0.66 min(HPLC-A) IV.26 IV.B

3,3a,4,5,6,6a- hexahydro-2H- cyclopenta[b]furan- 3-ol^((d)) 238 0.60 min(HPLC-B) IV.27 IV.B

3,3a,4,5,6,6a- hexahydro-2H- cyclopenta[b]furan- 4-ol^((d)) 238 0.58 min(HPLC-B) IV.28 IV.B

1,2- dimethylcyclopro- panol 196 0.80 min (HPLC-E) IV.29 IV.B

(1R,2R)-2- benzyloxycyclo- butanol 198 0.59 min (HPLC-E) IV.30 IV.B

3-benzyloxy-2,2- dimethyl- cyclobutanol 226 0.69 min (HPLC-E) IV.31 IV.B

(1R,2R)-2- methoxycyclo- pentanol 226 0.76 min (HPLC-E) IV.32 IV.B

oxetan-3-ol 184 *The synthesis is performed on the cis/trans mixture andthe desired isomer is isolated by HPLC

The following Intermediates are prepared in a similar manner tointermediate VI.1 by reduction from the corresponding startingmaterials:

ESI-MS Starting m/z Name Structure material R M + H⁺ R_(t)(HPLC) IV.35IV.B III.2

270 0.59 min (HPLC-H) IV.36 IV.B III.4

240 0.63 min (HPLC-M) IV.37 IV.B III.5

265 0.47 min (HPLC-A) IV.38 IV.B III.6

256 0.57 min (HPLC-M) IV.39 IV.B III.8

298 0.74 min (HPLC-M) IV.40 IV.B III.9

270 0.61 min (HPLC-M) IV.41 IV.B III.10

284 0.68 min (HPLC-M) IV.42 IV.B III.11

258 0.49 min (HPLC-A)

The following Intermediates are prepared according to the givenreferences:

Struc- Name ture R Reference IV.50 IV.A

WO 2011/104334 IV.51 IV.A

WO 2010/23181 IV.52 IV.A

WO 2011/104337 IV.53 IV.F

WO 2006/136402 IV.54 IV.B

WO 2011/104334 IV.55 IV.B

WO 2011/104337 IV.56 IV.B

WO 2011/104337 IV.57 IV.B

WO 2011/104334 IV.58 IV.B

WO 2011/104334 IV.59 IV.B

WO 2011/104338 IV.60 IV.B

U.S. Pat. No. 5,750,471 IV.61 IV.A

WO 2011/104337 IV.62 IV.B

WO 2011/104334

Intermediate IV.80: 2-[(3R)-tetrahydrofuran-3-yl]oxythiophen-3-amine

Is prepared in a similar manner as intermediate IV.1 from(3R)-tetrahydrofuran-3-ol and 2-chloro-3-nitro-thiophene

ESI-MS: m/z=186 (M+H)⁺, R_(t)(HPLC): 0.90 min (HPLC-D)

Intermediate IV.81: 2-[(3R)-tetrahydrofuran-3-yl]oxythiophen-3-amine

Step 1:

A mixture of THF and 2.4 g NaH (55% in mineral oil, 55 mmol) is cooledto 0° C., 5.2 ml tetrahydro-pyran-4-ol (55 mmol) are slowly added andthe mixture stirred for 30 minutes. 10.0 g (52 mmol)2,6-dichloro-3-nitro-pyridine in THF are slowly added and the mixture isstirred at RT over night. The reaction mixture is diluted with EtOAc andwater. The organic phase is separated and washed with water and brine,dried and evaporated. The residual is purified by FC, giving rise to 7.8g (58%) 6-chloro-3-nitro-2-(tetrahydro-pyran-4-yloxy)-pyridine.

Step 2:

A mixture of 1.2 g (4.6 mmol) of6-chloro-3-nitro-2-(tetrahydro-pyran-4-yloxy)-pyridine, 550 mg (4.7mmol) zinc cyanide, 260 mg (0.47 mmol)1,1′-bis(diphenylphosphino)-ferrocene, 215 mg (0.24 mmol) Pd₂dba₃ in DMFare stirred at 120° C. for 5 h and 100° C. over night. After cooling toRT, the reaction mixture is diluted with EtOAc, washed with 10% aq.K₂CO₃ solution, water and brine, dried and evaporated. The residual ispurified by FC, giving rise to 840 mg (73%)5-Nitro-6-(tetrahydro-pyran-4-yloxy)-pyridine-2-carbonitrile.

Step 3:

A mixture of 840 mg (3.4 mmol)5-Nitro-6-(tetrahydro-pyran-4-yloxy)-pyridine-2-carbonitrile, 3.2 g(16.9 mmol) SnCl₂ and EtOAc are heated to reflux for 1 h. After coolingto RT, the reaction mixture is diluted with EtOAc and washed with 10%aq. K₂CO₃ solution. The aqueous phase is separated and extracted withEtOAc. The organic phases are pooled and washed with 10% aq. K₂CO₃solution, water and brine, dried and evaporated. The residual ispurified by FC.

Yield: 420 mg (57%), ESI-MS: m/z=220 (M+H)⁺

Intermediate IV.82

Is prepared in a similar manner as intermediate IV.1 from(3S)-tetrahydrofuran-3-ol and 2,6-difluoro-3-nitro-pyridine

ESI-MS: m/z=199 (M+H)⁺, R_(t)(HPLC): 0.65 min (HPLC-E)

Intermediate IV.83

Step 1:

A mixture of THF and 320 mg (3.6 mmol) (3S)-tetrahydrofuran-3-ol iscooled to 0° C. and 145 mg (3.6 mmol) NaOH are added and the mixturestirred for 1 h. 700 mg (3.6 mmol) 2,6-dichloro-3-nitro-pyridine areslowly added and the mixture is stirred at RT for 3 days. The reactionmixture is filtered and evaporated The residual is purified by FC,giving rise to 600 mg (68%)6-chloro-3-nitro-2-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine.

Step 2:

A mixture of 600 mg (2.5 mmol)6-chloro-3-nitro-2-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine, 1.6 g (7.3mmol) SnCl₂ and EtOH are stirred at RT over night. The reaction mixtureis diluted with water and extracted with EtOAc. The organic phases arepooled dried and evaporated. The residual is purified by FC.

Yield: 500 mg (95%), ESI-MS: m/z=215 (M+H)⁺ Rt(HPLC): 0.83 min (HPLC-E)

The following Intermediates are prepared according to the givenreferences:

Name Structure Reference V.1

WO 2008/141843 V.2

WO 2008/141843 V.3

Adaptation of WO 2008/141843 V.4

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.5

WO 2008/141843 V.6

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.7

Adaptation of Org, Lett., 2004, 6(8), 1305-1307 V.8

US 2005/228027 V.9

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.10

WO 2008/141843 V.11

Adaptation of WO2011/29537 V.12

WO 2008/141843 V.13

Adaptation of THL, 1993, 34(1), 133-136 V.14

Adaptation of J. Org. Chem., 1974, vol, 39, 2458- 2459 V.15

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.16

Org. Lett., 2004, 6(8), 1305-1307 V.17

Adaptation of Oeg. Lett., 2004, 6(8), 1305-1307 V.18

Adaptation of Org. Lett., 2004, 6(8), 1305-1307 V.19

Org. Lett., 2007, Vol, 9, #19 3809-3811 V.20

Adaptation of WO 2008/141843 V.21

Adaptation of WO 2008/141843

Intermediate V.50

Step 1:

A mixture of 0.5 g (2.2 mmol)S,S-Dimethyl-N-[(phenylmethoxy)-carbonyl]sulfoximine (J. Org. Chem.,2005, 70 (23), 9599) and THF is cooled to −78° C. and 2.3 ml (2.3 mmol)LiHMDS 1M in THF is added dropwise and the mixture is stirred for 20minutes. 0.2 g (2.3 mmol) Ethyl formate in THF is added and the mixtureis stirred at −78° C. for 50 minutes warmed to RT and stirred foradditional 4 h. The Reaction mixture is diluted with water and EtOAc,the aqueous phase is separated and extracted with EtOAc. The organicphases are pooled and washed with water and brine, dried and evaporated.To a mixtue of the residual, 0.1 g (1.6 mmol) pyrrolidine and THF 0.1 gacetic acid and 0.4 g (2.0 mmol) NaBH(OAc)₃ are added and the reactionmixture is stirred at RT over night. The reaction mixture is evaporatedand purified by HPLC giving rise to benzylN—[methyl-oxo-(2-pyrrolidin-1-ylethyl)-λ⁶-sulfanylidene]carbamate.

Step 2:

A mixture of 0.1 g (0.193 mmol) benzylN-[methyl-oxo-(2-pyrrolidin-1-ylethyl)-λ⁶-sulfanylidene]carbamate and1.5 ml 48% HBr in water is stirred at RT for 5 h. The reaction mixtureis diluted with ether and the aqueous phase is evaporated. DCM is addedto the residual and the solution is neutralized with 1 M NaOH. Theaqueous phase is separated and evaporated giving rise to a mixture ofimino-methyl-oxo-(2-pyrrolidin-1-ylethyl)-λ⁶-sulfane and NaBr.

ESI-MS: m/z=177 (M+H)⁺, R_(t)(HPLC): 0.07 min (HPLC-W)

Intermediate V.51

Step 1:

A mixture of 0.3 g (1.32 mmol)S,S-Dimethyl-N-[(phenylmethoxy)-carbonyl]sulfoximine (J. Org. Chem.,2005, 70 (23), 9599) and THF is cooled to −78° C. and 1.3 ml (2.1 mmol)n-BuLi in hexane is added dropwise and the mixture is stirred at 1 h andthe warmed to −10° C. and added to a mixture of 0.3 g (1.6 mmol)dimethyl-methylene-ammonium iodide (Eschenmoser's salt) and THF. Themixture is stirred at 0° C. for 30 minutes warmed to RT and stirred overnight. The reaction mixture is evaporated and purified by HPLC givingrise to benzylN-(2-dimethylaminoethyl-methyl-oxo-λ⁶-sulfanylidene)carbamate TFA salt.

Step 2:

A mixture of 0.1 g (0.201 mmol) benzylN-(2-dimethylaminoethyl-methyl-oxo-λ⁶-sulfanylidene)carbamate TFA saltand 30% HBr in acetic acid is stirred at RT for 1.5 h. The reactionmixture is diluted with ether and evaporated. The residual is twiceco-evaporated with toluene giving rise to a mixture ofN,N-dimethyl-2-(methylsulfonimidoyl)ethanamine as HBr salt.

ESI-MS: m/z=151 (M+H)⁺, R_(t)(HPLC): 0.07 min (HPLC-W)

Intermediate VI.1:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenol

6.7 g (25 mmol) of II.2 and 5.7 g (26 mmol) of IV.60 is dissolved inacetic acid and heated to 100° C. for 1 h. After cooling to RT thereaction mixture is diluted with water and the precipitate is filteredoff and washed with water. The crude product is treated with 80 mlethanol, filtered and dried yieldingN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine.

Yield: 7.1 g (65%), ESI-MS: m/z=438 (M+H)⁺, R_(t)(HPLC): 1.12 min(HPLC-M)

3.1 g (7 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine, 0.8g (8.8 mmol) dimethylsulphoximine (V.1), 0.4 g (1.4 mmol)2-(di-t-butylphosphino) biphenyl, 0.5 g (0.5 mmol) Pd₂dba₃ and 1.0 g(10.2 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 4.5h. After cooling to RT the reaction mixture is filtered, diluted withwater and extracted with EtOAc. The organic layers are pooled dried andevaporated. The residue is purified by FC giving rise toN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-amine.

Yield: 2.8 g (88%), ESI-MS: m/z=451 (M+H)⁺

3.5 g (7.8 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-aminein DCM are cooled to 0° C., 0.9 ml (9.3 mmol) boron tribromide are addeddropwise and the reaction mixture is stirred for 15 min. Water is addedcautiously and the aqueous layer is separated and extracted with DCM.The organic phases are pooled, washed with water, dried and evaporated.The residue is treated with isopropanol, filtered and dried.

Yield: 2.5 g (89%), ESI-MS: m/z=361 (M+H)⁺, R_(t)(HPLC): 1.12 min(HPLC-T)

Intermediate VI.2:2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenol

Is prepared in a similar manner as intermediate VI.1 using II.2, IV.60and V.5.

ESI-MS: m/z=387 (M+H)⁺, R_(t)(HPLC): 0.56 min (HPLC-M)

Methods of Preparation of Final Compounds

General Procedure 1 (P1) for Examples Shown in Table 1 and Table 2:

Equimolar amounts of the respective intermediates II and IV aredissolved in AcOH and heated to the given temperature for the giventime. The reaction mixture is diluted with water and saturated aqueousNaHCO₃-solution. An alternative workup comprises evaporation of thereaction mixture and treatment of the residue with MeOH and water. Incase the product precipitates it is filtered off, otherwise the mixtureis extracted with EtOAc. The organic phases are pooled dried andevaporated. If required, the crude product is further purified by FC orHPLC. Another example for the reaction and work-up is the first step inthe synthesis of VI.1.

The following examples in table 1 (example number given in column #) areprepared according to P1, details are (liven in the column synthesiscomment.

TABLE 1 ESI-MS m/z R_(t) Synthesis # Structure II IV M + H⁺ HPLC comment1.1

II.9 IV.12 489 1.33 min HPLC-S 130° C. 6 h with ACN as cosolvent 1.2

II.5 IV.35 523 0.93 min HPLC-P 75° C. 3 h 1.3

II.5 IV.12 509 0.83 min HPLC-P 75° C. 3 h 1.4

II.5 IV.36 493 0.97 min HPLC-P 75° C. 3 h 1.5

II.11 IV.55 485 1.05 min HPLC-P 65° C. over night 1.6

II.5 IV.1 509 0.74 min HPLC-M 65° C. 3 h 1.7

II.7 IV.36 519 0.54 min HPLC-K 75° C. 3 h 1.8

II.7 IV.55 477 0.56 min HPLC-K 75° C. 3 h 1.9

II.9 IV.6 472 0.82 min HPLC-H 140° C. 4 h with ACN as cosolvent 1.10

II.9 IV.14 505 0.89 min HPLC-E 65° C. over night then 100° C. 6 h 1.11

II.6 IV.55 495 0.84 min HPLC-E 65° C. over night 1.12

II.9 IV.53 427 1.49 min HPLC-S 130° C. 6 h with ACN as cosolvent 1.13

II.7 IV.35 549 0.52 min HPLC-K 75° C. 3 h 1.14

II.5 IV.55 451 0.7 min HPLC-A 65° C. 3 h 1.15

II.10 IV.55 457 0.85 min HPLC-E 75° C. over night 1.16

II.5 IV.50 462 0.76 min HPLC-M 65° C. 4.5 h 1.17

II.5 IV.54 479 0.8 min HPLC-M p-TsOH salt of the aniline used. 65° C. 3h 1.18

II.9 IV.1 489 0.85 min HPLC-H 110° C. 6 h with ACN as cosolvent 1.19

II.13 IV.55 472 0.96 min HPLC-P 65° C. for 30 h 1.20

II.6 IV.12 567 0.70 min HPLC-V 80° C. over night 1.21

II.12 IV.55 467 0.86 min HPLC-E 80° C. for 3 h 1.22

II.14 IV.55 433 0.68 min HPLC-A 80° C. for 24 h 1.23

II.15 IV.55 483 0.91 min HPLC-P 65° C. for 2 h 1.24

II.15 IV.12 555 0.63 min HPLC-N 80° C. for 5 h 1.25

II.16 IV.55 473 0.79 min HPLC-I 80° C. for 4 h 1.26

II.17 IV.55 463 0.86 min HPLC-M 75° C. for 3 h 1.27

II.17 IV.36 505 0.69 min HPLC-N 80° C. for 4 h 1.28

II.9 IV.20 415 0.61 min HPLC-X 80° C. 5 h 1.29

II.9 IV.21 429 0.65 min HPLC-Z 80° C. 5 h 1.30

II.9 IV.22 483 0.64 min HPLC-X 80° C. 5 h 1.31

II.9 IV.23 431 0.36 min HPLC-Q 80° C. 8 h 1.32

II.9 IV.24 445 0.66 min HPLC-N 75° C. 5 h 1.33

II.9 IV.28 429 0.47 min HPLC-Q 80° C. 5 h 1.34

II.9 IV.29 431 0.46 min HPLC-K 80° C. 5 h 1.35

II.9 IV.30 459 0.72 min HPLC-V 80° C. 5 h 1.36

II.9 IV.31 459 0.93 min HPLC-E 80° C. 3 h 1.37

II.9 IV.61 427 0.68 min HPLC-E 80° C. 3 h 1.38

II.9 IV.81 453 0.72 min HPLC-V 75° C. for 4 days 1.39

II.9 IV.62 459 0.88 min HPLC-E 75° C. for 3 h 1.40

II.9 IV.82 432 0.81 min HPLC-E 75° C. for 3 h 1.41

II.9 IV.83 448 0.86 min HPLC-E 75° C. over nightGeneral Procedure 2 (P2) for Examples Shown in Table 2:

1 eq of aryl bromide, 1.2 eq sulphoximine, 25 mol %2-(di-t-butylphosphino) biphenyl, 8 mol % Pd₂dba₃ and 1.4 eq sodiumtert-butoxide are dissolved in dioxane and heated to the giventemperature for the given time. The reaction mixture is concentrated andthe crude product purified by HPLC or FC. Another example for thereaction and work-up is the second step in the synthesis of VI.1.

General Procedure 3 (P3) for Examples Shown in Table 2:

1 eq of aryl bromide, 1.25 eq sulphoximine, 20 mol % rac-BINAP, 15 mol %Pd(OAc)₂ and 1.4 eq Cs₂CO₃ are suspended in toluene and heated to heatedto the given temperature for the given time. The reaction mixture isconcentrated and the crude product purified by HPLC or FC.

To obtain the following examples shown in table 2 (example number givenin column #), the corresponding 7-bromo quinazoline (aryl bromide) isprepared according to P1 followed by coupling according to P2 or P3.Details are given in the column synthesis comment.

TABLE 2 ESI-MS m/z R_(t) Synthesis # Structure II IV M + H⁺ HPLC comment2.1

II.8 IV.35 519 0.74 min HPLC-M P2 80° C. 2.5 h 2.2

II.2 IV.1 531 0.82 min HPLC-P P2 80° C. 2 h 2.3

II.2 IV.55 473 0.77 min HPLC-I P2 80° C. 2 h 2.4

II.2 IV.6 498 0.64 min HPLC-J P2 80° C. 2.5 h 2.5

II.2 IV.56 431 0.56 min HPLC-C P2 80° C. 2 h with DMF as solvent 2.6

II.2 IV.51 428 1.5 min HPLC-S P3 100° C. over night 2.7

II.2 IV.41 517 0.67 min HPLC-A P2 80° C. 2 h 2.8

II.2 IV.80 445 1.16 min HPLC-D P2 80° C. 2 h 2.9

II.8 IV.35 545 0.78 min HPLC-M P2 80° C. 2.5 h 2.10

II.2 IV.4 541 0.79 min HPLC-A P2 80° C. 2 h 2.11

II.2 IV.36 536 0.93 min HPLC-P P2 80° C. 2 h 2.12

II.2 IV.57 501 0.47 min HPLC-Q P2 80° C. 2 h 2.13

II.1 IV.59 548 1.15 min HPLC-H P2 80° C. 2 h 2.14

II.2 IV.57 614 1.51 min HPLC-D P2 80° C. 2 h 2.15

II.1 IV.4 545 0.81 min HPLC-A P2 80° C. 2 h 2.16

II.2 IV.16 470 0.19 min HPLC-O P2 80° C. 2 h 2.17

II.2 IV.57 515 1.58 min HPLC-G P3 100° C. over night 2.18

II.8 IV.50 484 0.45 min HPLC-K P2 80° C. 2 h 2.19

II.2 IV.38 489 0.7 min HPLC-M P2 80° C. 2 h with DMF as solvent 2.20

II.2 IV.55 445 0.97 min HPLC-P P2 80° C. 2.5 h 2.21

II.2 IV.1 630 0.73 min HPLC- A) P2 80° C. 2 h 2.22

II.2 IV.54 473 0.75 min HPLC-I P2 80° C. 2 h 2.23

II.2 IV.5 527 0.79 min HPLC-A P2 80° C. 2 h 2.24

II.2 IV.15 454 0.65 min HPLC-A P2 80° C. 2 h 2.25

II.2 IV.9 487 0.66 min HPLC-N P2 80° C. 2 h 2.26

II.1 IV.58 477 0.64 min HPLC-R P2 80° C. 2 h with DMF as solvent 2.27

II.2 IV.59 544 1.12 min HPLC-H P2 80° C. 2 h 2.28

II.2 IV.39 531 0.8 min HPLC-M P2 80° C. 2 h 2.29

II.1 IV.7 433 0.83 min HPLC-C P2 80° C. 2 h 2.30

II.2 IV.37 498 0.62 min HPLC-A P3 110° C. 1 h. formed isomers separatedby HPLC 2.31

II.2 IV.50 442 0.8 min HPLC-P P2 80° C. 2 h 2.32

II.1 IV.8 534 0.78 min HPLC-A P2 80° C. 2 h 2.33

II.2 IV.1 503 0.66 min HPLC-J P2 80° C. 2 h 2.34

II.2 IV.35 503 0.57 min HPLC-N P2 80° C. 2.5 h 2.35

II.1 IV.10 477 0.68 min HPLC-C P2 80° C. 2 h 2.36

II.2 IV.1 515 0.83 min HPLC-P P2 80° C. 2 h 2.37

II.2 IV.41 543 0.7 min HPLC-A P2 80° C. 2 h 2.38

II.2 IV.55 494 0.96 min HPLC-P P2 80° C. 2 h 2.39

II.2 IV.36 473 0.67 min HPLC-A P2 80° C. 2 h 2.40

II.2 IV.54 485 0.63 min HPLC-N P2 80° C. 2.5 h 2.41

II.2 IV.1 533 0.56 min HPLC-N P2 80° C. 2 h 2.42

II.2 IV.36 499 0,.7 min HPLC-A P2 80° C. 2 h 2.43

II.2 IV.35 529 0.62 min HPLC-N P2 80° C. 2.5 h 2.44

II.2 IV.50 456 0.69 min HPLC-I P2 80° C. 2 h 2.45

II.2 IV.40 503 0.63 min HPLC-A P2 80° C. 1 h 2.46

II.1 IV.57 477 1.73 min HPLC-S P3 100° C. over night 2.47

II.2 IV.55 431 0.89 min HPLC-P P2 with DMF as solvent 80° C. 2 h 2.48

II.2 IV.57 499 0.49 min HPLC-L P2 80° C. 2 h 2.49

II.1 IV.3 460 0.22 min HPLC-O P2 80° C. 2 h 2.50

II.1 IV.35 533 0.79 min HPLC-M P2 80° C. 2.5 h 2.51

II.2 IV.1 529 0.37 min HPLC-L P2 80° C. 2 h 2.52

II.2 IV.8 530 0.77 min HPLC-A P2 80° C. 2 h 2.53

II.1 IV.52 418 0.55 min HPLC-C P2 80° C. 2 h 2.54

II.2 IV.54 549 0.77 min HPLC-A P2 80° C. 2 h 2.55

II.2 IV.35 517 0.77 min HPLC-M P2 80° C. 2 h 2.56

II.1 IV.57 519 1.72 min HPLC-G P3 100° C. over night 2.57

II.2 IV.55 572 1.39 min HPLC-D P2 80° C. 2 h 2.58

II.2 IV.80 419 1.11 min HPLC-D P2 80° C. 2 h 2.59

II.2 IV.8 556 0.92 min HPLC-M P2 80° C. 2 h 2.60

II.2 IV.9 461 0.75 min HPLC-I P2 80° C. 2 h 2.61

II.2 IV.37 498 0.65 min HPLC-A P3 110° C. 1 h. formed isomers separatedby HPLC 2.62

II.2 IV.11 473 0.52 min HPLC-C Racemate P2 80° C. 2 h with DMF assolvent 2.63

II.2 IV.55 475 0.99 min HPLC-P P2 80° C. 2.5 h 2.64

II.2 IV.55 493 1.09 min HPLC-P P2 80° C. 2 h 2.65

II.2 IV.17 466 0.72 min HPLC-I P2 80° C. 3 h 2.66

II.2 IV.59 570 0.96 min HPLC-M P2 80° C. 2 h 2.67

II.2 IV.58 473 0.24 min HPLC-L P2 80° C. 2 h with DMFas solvent 2.68

II.2 IV.3 456 0.22 min HPLC-O P2 80° C. 2 h 2.69

II.2 IV.50 468 0.7 min HPLC-J P2 80° C. 2.5 h 2.70

II.2 IV.7 429 0.79 min HPLC-C P2 80° C. 2 h 2.71

II.2 IV.54 459 0.88 min HPLC-P P2 80° C. 2 h 2.72

II.2 IV.55 493 0.73 min HPLC-N P2 80° C. 2 h 2.73

II.8 IV.54 475 0.46 min HPLC-K P2 80° C. 2 h 2.74

II.2 IV.10 473 0.65 min HPLC-C P2 80° C. 2 h 2.75

II.2 IV.57 473 0.75 min HPLC-A P2 80° C. 2 h with DMF as solvent 2.76

II.1 IV.35 507 0,.75 min HPLC-M P2 80° C. 2.5 h 2.77

II.1 IV.5 531 0.79 min HPLC-A P2 80° C. 2 h 2.78

II.2 IV.55 471 1.02 min HPLC-P P2 80° C. 2.5 h 2.79

II.8 IV.36 515 0.95 min HPLC-P P2 80° C. 2 h 2.80

II.2 IV.13 489 0.63 min HPLC-A P2 80° C. 2 h with DMF as solvent 2.81

II.2 IV.57 487 0.48 min HPLC-L P2 80° C. 2 h 2.82

II.2 IV.11 499 0.76 min HPLC-J Racemate P2 80° C. 2.5 h 2.83

II.2 IV.12 515 0.69 min HPLC-J P2 80° C. 2.5 h 2.84

II.2 IV.57 513 0.47 min HPLC-Q P2 80° C. 2 h 2.85

II.2 IV.55 457 0.78 min HPLC-I P2 80° C. 2 h 2.86

II.2 IV.1 517 0.85 min HPLC-P P2 80° C. 2 h 2.87

II.2 IV.57 517 0.78 min HPLC-N P2 80° C. 2 h 2.88

II.2 IV.2 470 0.81 min HPLC-E P2 80° C. 2 h 2.89

II.1 IV.55 435 0.96 min HPLC-P P2 80° C. 2 h 2.90

II.8 IV.54 501 0.48 min HPLC-K P2 80° C. 2 h 2.91

II.2 IV.2 444 0.35 min HPLC-Q P2 80° C. 2 h 2.92

II.2 IV.55 459 0.81 min HPLC-I P2 80° C. 2 h 2.93

II.2 IV.55 473 0.46 min HPLC-K P2 80° C. 2 h 2.94

II.2 IV.36 529 0.57 min HPLC-N P2 80° C. 2 h 2.95

II.2 IV.36 536 0.63 min HPLC-N P2 80° C. 2 h 2.96

II.2 IV.36 536 0.63 min HPLC-N P2 80° C. 2 h 2.97

II.2 IV.55 487 0.52 min HPLC-X P2 80° C. 2 h 2.98

II.2 IV.55 443 1.26 min HPLC-Y P2 80° C. 1 h 2.99

II.2 IV.36 543 0.39 min HPLC-Q P2 80° C. 2 h 2.100

II.2 IV.55 494 0.65 min HPLC-N P2 80° C. 2 h 2.101

II.2 IV.55 501 0.66 min HPLC-N P2 80° C. 2 h 2.102

II.2 IV.55 494 1.38 min HPLC-D P2 80° C. 2 h 2.103

II.2 IV.55 457 0.74 min HPLC-V P2 80° C. 2 h 2.104

II.2 IV.55 459 0.76 min HPLC-V P2 80° C. 2 h 2.105

II.2 IV.36 515 0.92 min HPLC-M P3 50° C. 3 d using Xantphos as ligand2.106

II.2 IV.36 485 1.38 min HPLC-D P2 90° C. 2 h 2.107

II.2 IV.54 542 0.41 min HPLC- W P2 80° C. 2 h 2.108

II.2 IV.36 515 0.73 min HPLC-N P2 80° C. 2 h 2.109

II.2 IV.36 501 0.67 min HPLC-N P2 80° C. 2 h 2.110

II.2 IV.54 471 1.18 min HPLC-D P2 80° C. over night 2.111

II.2 IV.55 484 0.99 min HPLC-E P2 80° C. 2 h 2.112

II.2 IV.55 473 0.82 min HPLC-V P2 80° C. 2 h 2.113

II.2 IV.54 516 0.39 min HPLC- W P2 80° C. 2 h 2.114

II.2 IV.36 499 0.64 min HPLC-N P2 80° C. 2 h 2.115

II.2 IV.50 545 1.15 min HPLC-F P2 80° C. 1 h 2.116

II.2 IV.42 491 0.67 min HPLC-A P2 80° C. 1 h 2.117

II.2 IV.42 517 0.68 min HPLC-A P2 80° C. 2 h 2.118

II.1 IV.18 508 0.64 min HPLC-B P2 80° C. over night 2.119

II.1 IV.18 520 0.64 min HPLC-B P2 80° C. over night 2.120

II.2 IV.19 447 0.66 min HPLC-V P2 80° C. over night 2.121

II.2 IV.25 473 0.64 min HPLC-A P2 90° C. 5 h 2.122

II.2 IV.26 471 0.7 min HPLC-B P2 80° C. 2 h 2.123

II.2 IV.26 497 0.73 min HPLC-B P2 80° C. 2 h 2.124

II.2 IV.27 471 0.7 min HPLC-B P2 80° C. 2 h 2.125

II.2 IV.27 497 0.73 min HPLC-B P2 80° C. 2 h 2.126

II.2 IV.32 417 0.74 min HPLC-M P2 80° C. 1 hGeneral Procedure 4 (P4) for Examples Shown in Table 3:

1 eq of the BOC-protected starting material are dissolved in a mixtureof DCM and the given amount of acid and stirred at RT for the giventime. The reaction mixture was concentrated and if necessary the crudeproduct purified by HPLC or FC.

To obtain the following examples (example number given in column #)shown in table 3, the corresponding compounds (example number given incolumn SM) are deprotected according to P4. Details are given in thecolumn synthesis comment.

TABLE 3 ESI-MS m/z R_(t) Synthesis # Structure SM M + H⁺ HPLC comment3.1

2.77 431 0.53 min HPLC-A 12 eq TFA over night 3.2

2.10 441 0.96 min HPLC-F 12 eq TFA over night then additional 6 eq TFA 4h 3.3

2.21 530 0.58 min HPLC-J 10 eq TFA over night 3.4

2.59 456 0.56 min HPLC-A 11 eq TFA over night 3.5

2.15 445 0.54 min HPLC -A 12 eq TFA over night then additional 6 eq TFA4 h 3.6

2.23 427 0.52 min HPLC-A 12 eq TFA over night 3.7

2.32 434 0.53 min HPLC-A 12 eq TFA over night 3.8

2.13 448 0.1 min  HPLC-A 12 eq TFA over night 3.9

2.27 444 0.76 min HPLC-H 11 eq TFA over night 3.10

2.14 514 1.16 min HPLC-D 10 eq TFA over night 3.11

2.52 430 0.52 min HPLC-A 12 eq TFA over night 3.12

2.66 470 0.57 min HPLC-A 11 eq TFA over night 3.13

2.57 472 0.63 min HPLC-A 10 eq TFA over night 3.14

4.15 430 0.27 min HPLC-Q 20 eq TFA over nightGeneral Procedure 5 (P5) for Examples Shown in Table 4:

To 1 eq of the corresponding phenol intermediate VI, 2 eq of the alcoholand 3 eq of triphenyl phosphine in THF 3 eqDi-tert.butylazodicarboxylate are added and the reaction mixture isstirred at RT over night. The reaction mixture is concentrated andpurified by HPLC or FC. Another example for the reaction and work-up isthe synthesis of III.6.

To obtain the following examples (example number given in column #)shown in table 4, the corresponding compounds are prepared from theintermediate VI and the respective alcohol according to P5. Details aregiven in the column synthesis comment.

TABLE 4 ESI-MS m/z R_(t) Synthesis # Structure VI M + H+ HPLC comment4.1

VI.1 457 0.94 min HPLC-I Mixture of cis/trans Isomers 4.2

VI.1 516 0.8 min  HPLC-I — 4.3

VI.1 445 0.75 min HPLC-I Racemic Mixture of cis/trans Isomers 4.4

VI.1 468 0.72 min HPLC-B — 4.5

VI.1 445 0.79 min HPLC-I — 4.6

VI.2 503 1.01 min HPLC-M — 4.7

VI.1 471 1.01 min HPLC-I — 4.8

VI.1 536 0.74 min HPLC-I — 4.9

VI.1 479 0.87 min HPLC-I — 4.10

VI.1 486 0.72 min HPLC-I — 4.11

VI.1 443 0.95 min HPLC-I Racemic Mixture of cis/trans Isomers 4.12

VI.1 473 0.86 min HPLC-I Racemic Mixture of cis/trans Isomers 4.13

VI.1 445 0.74 min HPLC-I — 4.14

VI.1 511 0.98 min HPLC-I Mixture of cis/trans Isomers 4.15

VI.1 530 0.96 min HPLC-E —General Procedure 6 (P6) for Examples Shown in Table 5:

1 eq of the corresponding aryl fluoride 1.3 eq Cs₂CO₃ in a mixture ofthe respective alcohol and dioxane with the ratio 1:4 is stirred at 120°C. in a pressure vessel for the given time. If necessary, additionalCs₂CO₃ and alcohol are added and the reaction is continued at 120° C.for the given time. The reaction mixture is diluted with water andextracted with EtOAc. The organic layers are pooled dried andevaporated. If required, the crude product is further purified by FC orHPLC. Another example for the reaction and work-up is the synthesis ofII.8.

To obtain the following examples (example number given in column #)shown in table 5, the corresponding compounds (example number given incolumn SM) are transformed according to P6. Details are given in thecolumn synthesis comment.

TABLE 5 ESI-MS m/z R_(t) Synthesis # Structure SM M + H⁺ HPLC comment5.1

2.89 461 0.72 min HPLC-A 120° C. 24 h. Additional EtOH added, then 120°C. 24 h 5.2

2.89 447 0.7 min  HPLC-A 120° C. over night. Additional MeOH and Cs₂CO₃added then 120° C. 24 h 5.3

2.46 489 1.32 min HPLC-F 120° C. over night. Additional MeOH and Cs₂CO₃added then 120° C. 24 h 5.4

2.46 503 1.37 min HPLC-F 120° C. overnight. Additional EtOH and Cs2CO3added then 120° C. 24 h 5.5

2.76 533 0.69 min HPLC-A 90° C. for 3 days 5.6

2.76 551 0.79 min HPLC-A 90° C. for 30 h 5.7

2.76 569 0.69 min HPLC-A 90° C. for 20 hGeneral Procedure 7 (P7) for Examples Shown in Table 6:

A mixture of 1 eq of the corresponding amine 1.2 eq methanesulfonylchloride and 2.5 eq triethyl amine in DCM is stirred at RT over night.The reaction mixture is washed with water and the organic layer isseparated and evaporated. If required, the crude product is furtherpurified by HPLC.

General Procedure 8 (P8) for Examples Shown in Table 6:

To 1 eq of the corresponding amine 2 eq(tert-butyldimethylsiloxy)acetaldehyde in DCM:MeOH 1:1, 3 eq sodiumtrisacetoxyborohydride and 1 eq of acetic acid are added and thereaction mixture is stirred at RT for the given time. The reactionmixture is diluted with water and extracted with DCM. The organic layersare pooled dried and evaporated. For the deprotection DCM is added tothe residue and 7.2 eq tetrabutylammonium fluoride are added. Thereaction mixture is stirred at RT for the given time and evaporated. Thecrude product is further purified by HPLC.

General Procedure 9 (P9) for Examples Shown in Table 6:

A mixture of 1 eq of the corresponding amine, the given amount ofalkylating agent and base in DMF is stirred at RT for the given time.The reaction mixture is evaporated and if required, the crude product isfurther purified by HPLC.

To obtain the following examples (example number given in column #)shown in table 6, the corresponding compounds (example number given incolumn SM) are transformed according to P7, P8 or P9. Details are givenin the column synthesis comment.

TABLE 6 ESI-MS m/z R_(t) Synthesis # Structure SM M + H⁺ HPLC comment6.1

3.8 492 0.54 min HPLC-A P8 over night, deprotection 3 d 6.2

3.8 526 0.21 min HPLC-O P7 6.3

3.12 548 0.81 min HPLC-M P7 6.4

3.4 520 0.47 min HPLC-L P9 1.3 eq 2-iodo- 1,1-difluoro- ethane, 2.0 eqK₂CO₃, RT over night, then 50° C. 5 d 6.5

3.6 499 1.01 min HPLC-P P9 4.1 eq 2,2- dimethyloxirane, 2.5 eq K₂CO₃,80° C. over night with acetonitrile as solvent 6.6

3.9 526 1.2 min  HPLC-P P9 1.5 eq trifluoro- methanesulfonic acid 2,2,2-trifluoro-ethyl ester, 1.6 eq K₂CO₃, RT over night 6.7

3.12 514 0.55 min HPLC-B P8 3 d, deprotection over night 6.8

3.9 522 0.93 min HPLC-P P7 6.9

3.9 488 0.86 min HPLC-P P8 3 d, deprotection over night 6.10

3.6 471 0.52 min HPLC-A P8 over night, deprotection 3 d 6.11

3.1 475 0.9 min  HPLC-F P8 over night, deprotection 3 d 6.12

3.8 530 0.4 min  HPLC-R P9 1.6 eq 3- chloromethyl- [1,2,4]oxadiazole,1.6 eq K₂CO₃, RT over night 6.13

3.8 530 1.24 min HPLC-P P9 1.5 eq trifluoro- methanesulfonic acid 2,2,2-trifluoro-ethyl ester, 1.6 eq K₂CO₃, RT over night 6.14

3.11 494 0.93 min HPLC-D P9 2.8 eq 2- bromo-1,1- difluoro-ethane, 3.9 eqtriethylamine, 120° C. 5 h μW with acetonitrile as solvent 6.15

3.7 478 0.53 min HPLC-A P8 over night, deprotection 3 d 6.16

3.7 498 0.55 min HPLC-A P9 2 eq 2-bromo- 1,1-difluoro- ethane, 4 eqtriethylamine, 120° C. 3 h μW with acetonitrile as solvent 6.17

3.11 474 0.53 min HPLC-A P8 over night, deprotection 3 d 6.18

3.4 534 0.77 min HPLC-J P7 6.19

3.1 503 0.88 min HPLC-M P9 4.2 eq 2,2- dimethyloxirane, 2.6 eq K2CO3,80° C. over night with acetonitrile as solvent 6.20

3.9 497 0.97 min HPLC-D P9 6 eq 3-bromo- propionitrile, 3 eq K2CO3, RTover night

Example 7.1

To 100 mg (0.16 mmol) of example 3.10 and 26 mg (0.32 mmol) 37% aqueousformaldehyde solution are dissolved in THF and 53 mg (0.24 mmol) sodiumtrisacetoxy borohydride are added. The reaction mixture is stirred at RTfor 3 days. Additional aqueous formaldehyde solution and sodiumtrisacetoxy borohydride are added and the reaction mixture is stirredfor an additional day. Water is added and the mixture is extracted withDCM. The organic phases are pooled, dried and evaporated.

Yield: 50 mg (60%), ESI-MS: m/z=528 (M+H)⁺, R_(t)(HPLC): 1.16 min(HPLC-D)

Example 7.2

To 100 mg (0.16 mmol) of example 3.10, 48 mg (0.48 mmol) triethyl amine,23 mg (19 mmol) DMAP in DCM 18 mg (0.18 mmol) acetic acid anhydride areadded. The reaction mixture is stirred at RT over night. Water is added,the organic phase is separated and evaporated. The crude product ispurified by HPLC.

Yield: 54 mg (51%), ESI-MS: m/z=556 (M+H)⁺, R_(t)(HPLC): 1.30 min(HPLC-D)

Example 7.3

100 mg (0.16 mmol) of example 3.10, 62 mg (0.48 mmol) diisopropyl ethylamine in THF are cooled to 10° C. and 18 mg (0.19 mmol) methylchloroformate are added. The reaction mixture is stirred at 10° C. for30 min then at RT over night. Water is added and the mixture extractedwith EtOAc. The organic layers are pooled, dried and evaporated. Thecrude product is purified by HPLC.

Yield: 3 mg (3%), ESI-MS: m/z=572 (M+H)⁺, R_(t)(HPLC): 1.38 min (HPLC-D)

Example 7.4

A mixture of 42 mg (0.21 mmol) 4-Nitrophenylchloroformate, 17 mg (0.26mmol) methylamine hydrochloride and 59 mg (0.56 mmol) sodium carbonatein acetonirile are stirred at RT for 4 h. 100 mg (0.16 mmol) of Example3.10 and 48 mg (0.48 mmol) triethyl amine are added. The reactionmixture is stirred at RT over night and evaporated. The crude product ispurified by HPLC.

Yield: 22 mg (20%), ESI-MS: m/z=571 (M+H)⁺, R_(t)(HPLC): 0.43 min(HPLC-Q)

Example 7.5

A mixture of 100 mg (0.16 mmol) of example 3.10, 57 mg (0.56 mmol)triethyl amine and 21 mg (0.19 mmol) dimethyl carbamoyl chloride in DCMis stirred at RT over night. Additional triethyl amine and dimethylcarbamoyl chloride are added and the reaction mixture is stirred for 24h at RT. Water is added, the organic phase is separated and evaporated.The crude product is purified by HPLC.

Yield: 59 mg (64%), ESI-MS: m/z=585 (M+H)⁺, R_(t)(HPLC): 0.84 min(HPLC-I)

Example 7.6

A mixture of 50 mg (0.1 mmol) of example 1.10, 12 mg (0.1 mmol) zinccyanide, 6 mg (10 μmol) 1,1′-bis(diphenylphosphino)ferrocene, 5 mg (5μmol) Pd₂dba₃ in DCM are stirred at 120° C. for 2 h and 110° C. overnight. After cooling to RT the reaction mixture is filtered and purifiedby HPLC.

Yield: 34 mg (76%), ESI-MS: m/z=452 (M+H)⁺, R_(t)(HPLC): 0.39 min(HPLC-L)

Example 7.7

A mixture of 50 mg (0.1 mmol) of Example 1.11, 24 mg (0.1 mmol)2,4,6-trivinylcyclotriboroxane pyridine complex, 12 mg (10 μmol)tetrakis(triphenylphosphino)palladium(0), 3 mg (10 μmol) triphenylphosphine and 32 mg (0.3) mmol K₂CO₃ in DMF is heated in a microwave at120° C. for 40 min. After cooling to RT the reaction mixture is filteredand purified by HPLC.

Yield: 12 mg (28%), ESI-MS: m/z=443 (M+H)⁺, R_(t)(HPLC): 0.41 min(HPLC-L)

Example 7.8

20 mg 10% Pd/C are added to of 66 mg (0.15 mmol) of Example 7.7, inMeOH. The reaction mixture is stirred at RT for 3 days under a hydrogenatmosphere (50 psi). The catalyst is filtered off, the filtrate isevaporated and the crude product purified by HPLC.

Yield: 4 mg (5%), ESI-MS: m/z=445 (M+H)⁺, R_(t)(HPLC): 0.84 min (HPLC-E)

Example 7.9

A mixture of 60 mg (0.12 mmol) of example 1.11, 14 mg (0.12 mmol) zinccyanide, 7 mg (12 μmol) 1,1′-bis(diphenylphosphino)ferrocene, 6 mg (6μmol) Pd₂dba₃ in DMF are stirred at 120° C. for 4 h. After cooling to RTthe reaction mixture is filtered and purified by HPLC.

Yield: 31 mg (57%), ESI-MS: m/z=442 (M+H)⁺, R_(t)(HPLC): 0.94 min(HPLC-P)

Example 7.10

To 786 mg (1.81 mmol) of example 2.89 in NMP, 152 mg (2.17 mmol) NaSMein NMP is added and the reaction mixture is stirred at RT for 1 h,additional 152 mg (2.17 mmol) NaSMe in NMP is added and the reactionmixture is stirred at RT over night, 76 mg (1.9 mmol) NaSMe in NMP isadded and the reaction mixture is heated to 50° C. for 4 h. Aftercooling to RT the reaction mixture is diluted with water and extractedwith DCM. The organic phases are pooled dried and evaporated. The crudeproduct is purified by FC.

Yield: 528 mg (63%), ESI-MS: m/z=463 (M+H)⁺, R_(t)(HPLC): 0.57 min(HPLC-W)

Example 7.11

A mixture of 75 mg (0.16 mmol) of example 7.10 and DCM is cooled to 0°C., 41 mg (0.18 mmol) meta-chloroperoxybenzoic is added in portions. Thereaction mixture is stirred at RT for 1 h, the reaction mixture isdiluted with saturated NaHCO₃-solution and extracted with DCM. Theorganic phases are pooled dried and evaporated. The crude product ispurified by HPLC giving rise to the sulfoxide-intermediate (ESI-MS:m/z=479 (M+H)⁺, R_(t)(HPLC): 0.85 min (HPLC-E)).

To 0.1 g (0.28 mmol) XtalFluor-E in DCM, 0.1 g (0.38 mmol) triethylaminetrihydroflouride is added and the mixture is cooled to 0° C. 45 mg (0.09mmol) of the sulfoxide-intermediate in DCM is added dropwise. After 30min at 0° C. the reaction mixture is warmed to RT and stirred for 4days. Additional 0.1 g (0.28 mmol) XtalFluor-E and 0.1 g (0.38 mmol)triethylamine trihydroflouride are added and the reaction miture isheated to 50° C. for 4 h. After cooling to RT the reaction mixture isdiluted with water and extracted with DCM. The organic phases are pooleddried and evaporated. The crude product is purified by HPLC.

Yield: 10 mg (22%), ESI-MS: m/z=481 (M+H)⁺, R_(t)(HPLC): 0.93 min(HPLC-M)

Example 7.12

10.0 g (22.8 mmol) ofN-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine, inDCM are cooled to 0° C., 34.2 ml (34.2 mmol) boron tribromide are addeddropwise and the reaction mixture is stirred for 6 h. Water is addedcautiously and the precipitate is filtered off, suspended in water andneutralized with ammonia and stirred at RT for 2 h. The precipitate isfiltered and dried.

Yield: 7.2 g (91%), ESI-MS: m/z=348 (M+H)⁺, R_(t)(HPLC): 0.81 min(HPLC-E)

To a mixture of 500 mg (1.4 mmol)2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol, 1.7 g (14.4mmol) cyclopropyl bromide, 1.4 g (4.31 mmol) Cs₂CO₃, 0.1 g KI (0.43mmol), 0.1 ml (0.72 mmol) diisopropyl-ethyl-amine and dimethylacetamideis warmed to 150° C. and stirred over night. The reaction mixture isfiltered and purified via HPLC.

Yield: 130 mg (23%), ESI-MS: m/z=388 (M+H)⁺, R_(t)(HPLC): 0.95 min(HPLC-E)

60 mg (0.16 mmol) of7-bromo-N-[2-(cyclopropoxy)-4-fluoro-phenyl]-5-methyl-quinazolin-4-amine,18 mg (0.19 mmol) dimethylsulphoximine (V.1), 9 mg (0.03 mmol)2-(di-t-butylphosphino) biphenyl, 11 mg (0.01 mmol) Pd₂dba₃ and 22 mg(0.23 mmol) sodium tert-butoxide in dioxane are heated to 80° C. for 3h. After cooling to RT the reaction mixture is filtered and purified byHPLC.

Yield: 25 mg (41%), ESI-MS: m/z=401 (M+H)⁺, R_(t)(HPLC): 0.95 min(HPLC-N)

Example 7.13 and Example 7.14

Separation of the diastereomers obtained in example 2.20 (16 mg; 0.037mmol), the absolute configuration is not determined. HPLC: Agilent 1260with Aurora A5 Fusion and DA-detector, Chiralcel OZ—H 4.6×250 mm, 5 μm(Daicel), 40° C., 150 bar backpressure, 60% scCO₂, 40% MeOH+0.2% DEA, 4ml/min

Isomer 1, Example 7.13: Yield: 7 mg (43%), R_(t)(HPLC): 4.19 min

Isomer 2, Example 7.14: Yield: 7 mg (43%), R_(t)(HPLC): 5.44 min

Example 7.15

To 25 mg (0.06 mmol) of example 3.14 and 20 mg (0.24 mmol) 37% aqueousformaldehyde solution are dissolved in MeOH and 15 mg (0.24 mmol) sodiumtrisacetoxy borohydride are added. The reaction mixture is stirred at RTover night, diluted with DMF and purified by HPLC.

Yield: 17 mg (52%), ESI-MS: m/z=458 (M+H)⁺, R_(t)(HPLC): 0.28 min(HPLC-D)

Example 7.16

A mixture of 150 mg (0.33 mmol) of example 1.36 and DCM is cooled to 0°C. and 0.49 ml (0.45 mmol) of a 1 M solution of boron tribromide in DCMare added slowly. The reaction mixture is stirred at RT for 6 h, dilutedwith water, evaporated and purified by HPLC.

Yield: 120 mg (65%), ESI-MS: m/z=445 (M+H)⁺, R_(t)(HPLC): 0.84 min(HPLC-E)

Example 7.17

To A mixture of 50 mg (0.11 mmol) of example 1.39 and DCM 25 mg (0.15mmol) diethylaminosulfur trifluoride are added. The reaction mixture isstirred at RT over night, diluted with saturated aq. NaHCO₃ solution andthe mixture is extracted with DCM. The organic phases are pooledevaporated and the residual is purified by HPLC.

Yield: 28 mg (45%), ESI-MS: m/z=461 (M+H)⁺, R_(t)(HPLC): 0.44 min(HPLC-Q)

Example 7.18

Step 1:

To a mixture of 0.6 g (4.8 mmol) isoxazolidin-4-ol hydrochloride 1.7 ml(12 mmol) triethylamine and DCM 2.6 g (12 mmol) Boc₂O are added. Thereaction mixture is stirred at RT over night, diluted with water andEtOAc. The organic phase is separated, dried and evaporated and theresidual is purified by HPLC giving rise to tert-butyl4-hydroxyisoxazolidine-2-carboxylate.

Yield: 95 mg (11%), ESI-MS: m/z=190 (M+H)⁺

Step 2:

To a mixture of 0.4 g (2.11 mmol) tert-butyl4-hydroxyisoxazolidine-2-carboxylate, pyridine, DCM and a catalyticamount of DMAP 0.6 g (2.54 mmol) 3-nitrobenzenesulfonyl chloride areadded. The reaction mixture is stirred at RT over night, washed withsaturated aq. NaHCO₃ solution and water, dried and evaporated and theresidual is purified by FC giving rise to tert-butyl4-(3-nitrophenyl)sulfonyloxyisoxazolidine-2-carboxylate.

Yield: 0.2 g (10%), ESI-MS: m/z=392 (M+NH₄)⁺

Step 3:

A mixture of 0.2 g (0.21 mmol) tert-butyl4-(3-nitrophenyl)sulfonyloxyisoxazolidine-2-carboxylate 0.1 g (0.26mmol) intermediate VI.1, 0.1 g (0.256 mmol) Cs₂CO₃ and DMPU is stirredat RT over night. The reaction mixture is diluted with water andextracted with DCM. The organic phase is separated and evaporated. Theresidual is purified by HPLC giving rise to tert-butyl4-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]isoxazolidine-2-carboxylateas TFA salt.

Yield: 80 mg (58%), ESI-MS: m/z=532 (M+H)⁺

Step 4:

A mixture of 80 mg (0.124 mmol) tert-butyl4-[2-[[7-[[dimethyl(oxo)-λ⁶-sulfanylidene]amino]-5-methyl-quinazolin-4-yl]amino]-5-fluoro-phenoxy]isoxazolidine-2-carboxylateTFA salt, 4M HCl in dioxane and DCM is stirred at RT for 2 h. Thereaction mixture is evaporated and the residual is purified by HPLC.

Yield: 40 mg (59%), ESI-MS: m/z=432 (M+H)⁺, R_(t)(HPLC): 0.69 min(HPLC-B)

The invention claimed is:
 1. A compound of formula

wherein Ar is selected from the group consisting of:

wherein X is CH or N; Y is S, O or NH; R³ is H, halogen, CN or—C(═O)—NH₂; and R⁴ is selected from the group consisting of: a)C₃₋₇-cycloalkyl or C₃₋₇-cycloalkenyl, which may each be substituted withone to three substituents independently selected from the groupconsisting of halogen, CN, OH, CF₃, NH₂, —NH(C₁₋₃-alkyl),—N(C₁₋₃-alkyl)₂, —NH—C(═O)—(C₁₋₃-alkyl), —NH—C(═O)—O—(C₁₋₄-alkyl),—NH—SO₂—(C₁₋₃-alkyl), C₁₋₃-alkyl optionally substituted with 1 to 3F,C₃₋₇-cycloalkyl, —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl), —O—(C₁₋₃-alkyloptionally substituted with 1 to 3F, —COOH, —C(═O)—O—(C₁₋₄-alkyl),—C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) and —C(═O)—N(C₁₋₃-alkyl)₂; b)C₄₋₇-cycloalkyl optionally substituted with C₁₋₃-alkyl, wherein in thecylcoalkyl moiety, one or two methylene groups are replaced with a groupindependently selected from —C(═O)—, O, S, SO, SO₂ or NR⁷, wherein R⁷ isH, —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH—(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂,—SO₂—(C₁₋₃-alkyl), —SO₂—NH—(C₁₋₃-alkyl), —SO₂—N(C₁₋₃-alkyl)₂, orC₁₋₅-alkyl optionally substituted with one to three F and/or one CN, OHor heterocyclyl; and c) a bicycle selected from:

wherein Z₁, Z₂ and Z₃ are independently selected from among O and CR⁸R⁹,with the proviso that either Z₁, Z₂ and Z₃ are all CR⁸R⁹ or that one ofZ₁, Z₂ and Z₃ is O and the remaining Z₁-Z₃ are CR⁸R⁹, wherein R⁸ is H,halogen, OH, CN or —O—(C₁₋₃-alkyl); and R⁹ is H or C₁₋₃-alkyl; andwherein one of X₁, X₂, X₃ and X₄ is N and the other three of X₁, X₂, X₃and X₄ are CH; R¹ is

wherein R⁵ is selected from the group consisting of: a) C₁₋₄-alkyl,which is optionally substituted with —O—(C₁₋₃-alkyl),—O—C₃₋₇-cycloalkyl, —O-heterocyclyl, C₃₋₇-cycloalkyl, heterocyclyl orphenyl, wherein each alkyl group is optionally substituted with one ormore F; and b) C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl,heterocyclyl, heteroaryl and aryl; and R⁶ is C₁₋₃-alkyl which isoptionally substituted with one or more F; or wherein R⁵ and R⁶ togetherwith the sulfur atom to which they are attached form a 4- to 7-memberedsaturated or partly unsaturated heterocycle that further to the sulfuratom may contain one O, S or NR^(N), wherein R^(N) is H, C₁₋₃-alkyl,—C(═O)—(C₁₋₃-alkyl), —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂,—C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl); andwherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶ together withthe sulfur atom to which they are attached may each be independentlysubstituted with halogen, CN, OH, NH₂, —NH(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)₂,—NH—C(═O)—(C₁₋₄-alkyl), —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—C(═O)—NH₂,—NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,—N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—NH₂, —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl), C₁₋₆-alkyl,C₃₋₇-cycloalkyl, heterocylcyl, heteroaryl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,—(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl); —SO—(C₁₋₄-alkyl) or—SO₂—(C₁₋₄-alkyl); and R² is halogen, CN, OH, NH₂, C₁₋₃-alkyl,C₂₋₃-alkenyl, C₂₋₃-alkinyl, C₃₋₇-cycloalkyl, azetidinyl, oxetanyl,—O—C₁₋₃-alkyl, —O-cyclopropyl, —O-azetidinyl, —S—C₁₋₃-alkyl,—S-cyclopropyl or —S-azetidinyl, wherein each alkyl group is optionallysubstituted with one or more F; and wherein, if not otherwise specified,each alkyl group in the above definitions may be substituted with one tothree F; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1, wherein R¹ is selected from the group consistingof:

wherein R⁵ is selected from the group consisting of: a) C₁₋₄-alkyl,which is optionally substituted with —O—(C₁₋₃-alkyl), cycloalkyl,C₃₋₇-cycloalkyl, or phenyl, wherein each alkyl group is optionallysubstituted with one or more F; and b) C₃₋₇-cycloalkyl,tetrahydropyranyl, pyridinyl, and phenyl; and R⁶ is C₁₋₃-alkyl which isoptionally substituted with one or more F; or wherein R⁵ and R⁶ togetherwith the sulfur atom to which they are attached form a 4- to 7-memberedsaturated or partly unsaturated heterocycle that further to the sulfuratom may contain one O, S or NR^(N), wherein R^(N) is H, C₁₋₃-alkyl,—C(═O)—(C₁₋₃-alkyl), —C(═O)—O—(C₁₋₄-alkyl), —C(═O)—NH₂,—C(═O)—NH(C₁₋₃-alkyl), —C(═O)—N(C₁₋₃-alkyl)₂ or —SO₂(C₁₋₄-alkyl); andwherein R⁵, R⁶ and the heterocycles formed by R⁵ and R⁶ together withthe sulfur atom to which they are attached may each be independentlysubstituted with F, Cl, Br, CN, OH, NH₂, —NH(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)₂, —NH—C(═O)—(C₁₋₄-alkyl), —NH—C(═O)—O—(C₁₋₄-alkyl),—NH—C(═O)—NH₂, —NH—C(═O)—NH—(C₁₋₄-alkyl), —NH—C(═O)—N(C₁₋₄-alkyl)₂,—N(C₁₋₄-alkyl)-C(═O)—(C₁₋₄-alkyl), —N(C₁₋₄-alkyl)-C(═O)—O—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—NH₂, —N(C₁₋₄-alkyl)-C(═O)—NH—(C₁₋₄-alkyl),—N(C₁₋₄-alkyl)-C(═O)—N(C₁₋₄-alkyl)₂, —O—(C₁₋₄-alkyl), C₁₋₆-alkyl,C₃₋₇-cycloalkyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,—C(═O)—NH₂, —C(═O)—NH(C₁₋₄-alkyl), —C(═O)—N(C₁₋₄-alkyl)₂, —COOH,—C(═O)—O—(C₁₋₄-alkyl), —(C₁₋₄-alkyl)-NH—C(═O)—(C₁₋₄-alkyl),—SO—(C₁₋₄-alkyl) or —SO₂—(C₁₋₄-alkyl), or a pharmaceutically acceptablesalt thereof.
 3. A compound according to claim 1, wherein R² is selectedfrom the group consisting of F, Cl, Br, CN, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₂₋₃-alkenyl, —O—C₁₋₃-alkyl and —S—C₁₋₃-alkyl, wherein each alkyl groupis optionally substituted with one or more F; or a pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 1, wherein Aris selected from the group consisting of:

wherein R⁴ is as defined in claim 1; or a pharmaceutically acceptablesalt thereof.
 5. A compound according to claim 1, wherein Ar is selectedfrom the group consisting of:

wherein R³ is H, F, Cl, Br, CN or —C(═O)—NH₂, and R⁴ is as defined inclaim 1; or a pharmaceutically acceptable salt thereof.
 6. A compoundaccording to claim 5, wherein R³ is F; or a pharmaceutically acceptablesalt thereof.
 7. A compound according to claim 1, wherein R⁴ is selectedfrom the group consisting of: a) C₃₋₆-cycloalkyl, which is optionallysubstituted with one F, CN, OH, CH₃, CF₃, NH₂, —NH(C₁₋₃-alkyl),—N(C₁₋₃-alkyl)₂, —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃, C₁₋₃-alkyl,—O—(C₁₋₃-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) or—C(═O)—N(C₁₋₃-alkyl)₂ and may additionally be substituted with one F orCH₃; b) C₅₋₇-cycloalkyl optionally substituted with one CH₃, wherein inthe cylcoalkyl moiety, one methylene group is replaced with O, S, or NR⁷and a second methylene group may be replaced with O or —C(═O)—, whereinR⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ or C₁₋₄-alkyl optionallysubstituted with one to three F and/or one CN, OH or oxadiazolyl; and c)a bicycle selected from:

wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and R⁹ is H or CH₃; or apharmaceutically acceptable salt thereof.
 8. A compound according toclaim 1, wherein Ar is selected from the group consisting of:

wherein X is CH or N; R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; and R⁴ isselected from a group consisting of: a) C₃₋₆-cycloalkyl, which isoptionally substituted with one F, CN, OH, CH₃, CF₃, NH₂,—NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂, —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃,C₁₋₃-alkyl, —O—(C₁₋₃-alkyl) or —C(═O)—NH₂, and may additionally besubstituted with one F or CH₃; b) C₅₋₇-cycloalkyl optionally substitutedwith one CH₃, wherein in the cylcoalkyl moiety, one methylene group isreplaced with O, S, or NR⁷ and a second methylene group may be replacedwith O or —C(═O)—, wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ orC₁₋₄-alkyl optionally substituted with one to three F and/or one CN, OHor oxadiazolyl; and c) a bicycle selected from:

wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and R⁹ is H or CH₃; R¹ isselected from the group consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₃-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl, wherein the alkylgroup is optionally substituted with —O—(C₁₋₃-alkyl) or phenyl; and R⁶is C₁₋₃-alkyl; or wherein R⁵ and R⁶ together with the sulfur atom towhich they are attached form a 4- to 6-membered saturated heterocyclethat further to the sulfur atom may contain one O, S or NR^(N), whereinsaid heterocylcle is optionally substituted with OH or —O—CH₃; andwherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),—C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃; and R² is selected from the groupconsisting of F, Cl, Br, C₁₋₂-alkyl, cyclopropyl, —CH═CH₂ and—O—C₁₋₂-alkyl, wherein each alkyl group is optionally substituted withone to three F; or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 1, wherein Ar is selected from the groupconsisting of:

wherein R⁴ is selected from the group R⁴-G5b consisting of:

R¹ is selected from the group consisting of:

R² is F, C₁ or CH₃; or a pharmaceutically acceptable salt thereof.
 10. Acompound according to claim 1, wherein Ar is selected from the groupconsisting of:

wherein R³ is H, F, Cl, Br, CN or —C(═O)—NH₂; preferably, R³ is F; andR⁴ is selected from a group consisting of: a) C₃₋₆-cycloalkyl, which isoptionally substituted with one F, CN, OH, CH₃, CF₃, NH₂,—NH(C₁₋₃-alkyl), —N(C₁₋₃-alkyl)₂, —NH—C(═O)—O—(C₁₋₄-alkyl), —NH—SO₂—CH₃,C₁₋₃-alkyl, —O—(C₁₋₃-alkyl) or —C(═O)—NH₂, and may additionally besubstituted with one F or CH₃; b) C₅₋₇-cycloalkyl optionally substitutedwith one CH₃, wherein in the cylcoalkyl moiety, one methylene group isreplaced with O, S, or NR⁷ and a second methylene group may be replacedwith O or —C(═O)—, wherein R⁷ is H, —C(═O)—O—(C₁₋₄-alkyl), —SO₂—CH₃ orC₁₋₄-alkyl optionally substituted with one to three F and/or one CN, OHor oxadiazolyl; and c) a bicycle selected from:

wherein R⁸ is H, OH, CN or —O—(C₁₋₃-alkyl); and R⁹ is H or CH₃; R¹ isselected from the group consisting of:

wherein R⁵ is selected from the group consisting of C₁₋₄-alkyl,cyclopropyl, tetrahydropyranyl, pyridinyl and phenyl, wherein the alkylgroup is optionally substituted with —O—(C₁₋₃-alkyl) or phenyl; and R⁶is C₁₋₃-alkyl; or wherein R⁵ and R⁶ together with the sulfur atom towhich they are attached form a 4 to 6-membered saturated heterocyclethat further to the sulfur atom may contain one O, S or NR^(N), whereinsaid heterocylcle is optionally substituted with OH or —O—CH₃; andwherein R^(N) is H, CH₃, —C(═O)—CH₃, —C(═O)—O—(C₁₋₄-alkyl),—C(═O)—N(CH₃)₂ or —C(═O)—NH—CH₃; and R² is selected from the groupconsisting of F, Cl, Br, C₁₋₂-alkyl, cyclopropyl, —CH═CH₂ and—O—C₁₋₂-alkyl, wherein each alkyl group is optionally substituted withone to three F; or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable carrier.
 12. A pharmaceutical compositionaccording to claim 11 further comprising an additional therapeuticagent, wherein the additional therapeutic agent is selected from anantidiabetic agent, a lipid lowering agent, a cardiovascular agent, anantihypertensive agent, a diuretic agent, a thrombocyte aggregationinhibitor, an antineoplastic agent or an anti-obesity agent.